Parkinson's Disease

Question 1

What is parkinson’s disease?

Answer 1

Progressive neurodegenerative disorder

Question 2

What are the classical symptoms of PD?

Answer 2

Muscle rigidity/ stiffness
Resting rhythmic tremor
Bradykinesia (slowing of physical movement)
Postural instability/ abnormality
Secondary sy; depression, dementia or confusion, speech and swallowing difficulties, drooling, dizziness, impotence, urinary frequency, constipation

Question 3

What is the basal ganglia?

Answer 3

Collection of subcortical nuclei situated within each cerebral hemisphere, and upper brain stem

Includes; 
Caudate
Putamen
Globus pallidus (internal and external) 
Subthalamic nucleus
Substantia nigra; pars compacta and reticulata

Question 4

What is the role of the basal ganglia within the motor system?

Answer 4

Act on the cortex via thalamus
Basal ganglia receives inputs from all cortical areas (not just motor)
Projects to thalamus and then to cortical regions involved in motor planning

Question 5

Describe basal ganglia connection in a simplified manner

Answer 5

Major input to striatum from cerebral cortex

Cortical information is processed in striatum and passed to the internal segment of GP and SNpr

Question 6

What are the neuropathological hallmarks of PD?

Answer 6

Loss of nigrostriatal DA neurons (pars compacta of substantia nigra)
Presence of Lewy bodies (intraneuronal proteinaceous cytoplasmic inclusions)

Question 7

Describe the substantia nigra (pars compacta) in PD

Answer 7

Cell bodies of nigrostriatal DA neurons are in SNpc and project to the putamen (striatum)

SNpc normally contains approx 400,000 nerve cells which contain neuromelanin

Loss of DA neurons results in classical neuro-pathological trait of SNpc depigmentation

Loss of projection to putamen results in DA depletion in putamen

Onset of PD symtpoms; putamental DA depleted 80% and 60% of SNpc DA neurons lost

Question 8

Describe the neurochemical changes seen in PD

Answer 8

Loss of NA neurons of locus coerulous
Loss of 5HT neurons in the midline rahpe nucleus
Loss of ACh neurons in dorsal motor nucleus of vagus
Other regions affected; cerebral cortex, olfactory bulb, ANS, hippocampus

Question 9

What are lewy bodies?

Answer 9

Intracellular structures
Circular, with a dense protein core surrounded by a peripheral halo
Highly filamentous bodies (5-20 nm)
Contains ubiquitin and neurofilament proteins
Alpha-synuclein

Question 10

What is alpha synuclein?

Answer 10

Small hydrophilic protein (140 amino acids) that belongs to a family of related synucleins (beta and gamma)
Natively unfolded protein; has significant structural plasticity
Can aggregate to form insoluble filaments; Lewy bodies

Question 11

What determines the structural plasticity of alpha synuclein?

Answer 11

Dependent on the environment; it can be unfolded, form monomers/ oligomers or amyloidogenic filaments

Question 12

With what structure in AD are Lewy bodies similar too?

Answer 12

Beta amyloid or tau

Question 13

Is there a genetic component to PD?

Answer 13

Yes; in around 1% of PD patients; there is a pure autosomal trait 
Early onset (<40 yrs)
10 distinct genetic loci associated with PD with mutations in more than 4 genes

Question 14

What are some of the loci and genes implicated in PD?

Answer 14

PARK1; SNCA

PARK2; parkin

Question 15

Is there a physiological function of alpha synuclein?

Answer 15

Highly expressed in mammalian brain - particularly in the presynaptic nerve terminal

a-synuclein -/- mice show that is shows a role in synaptic vesicle recycling and DA neurotransmission

In vitro studies have implicated it in synaptic vesicle recycling as it can bind to acidic phospholipid vesicles

Alpha synuclein plays an important role in regulating synaptic vesicle size and recycling particularly relevant to the storage of nT

Question 16

What are the key changes seen in alpha synuclein mutant proteins?

Answer 16

Self aggregates more readily than WT
Suggests that aggregation of alpha-synuclein is a key event in the pathogenesis of PD
Transgenic mice with mutant alpha synuclein have Lewy body formation and neurodegeneration

Micro expression of A53T mutation develop intraneuronal inclusions, mitochondrial DNA damage and apoptosis of neocortical, brain stem and motor neurons

Over-expression of wt or mutant alpha synuclein in vitro increases ROS production and results in enhanced cell death

Question 17

Describe lewy body formation

Answer 17

Unfolded or disordered alpha synuclein monomers form beta sheet rich oligomers
Protofibrils give rise to more stable amyloid like fibrillar structures
Alpha synuclein fibrils aggregate to form lewy bodies

Question 18

Describe the role of parkin in PD pathogensis

Answer 18

Parkin is an enzyme; E3 ligase. 465 aa protein. E3 ubiquitin ligase
50% of early onset PD is linked to parkin mutations
Parkin mutations result in a loss of function of parkins E3 ligase activity leading to improper targeting of substrates for proteasomes degradation leading to potentially toxic accumulations in neurons

Question 19

What role do E3 ubiquitin ligases play?

Answer 19

Enzyme that tags target proteins with ubiquitin for degradation

Question 20

Describe the genetic link between ubiquitin and PD

Answer 20

UCH-L1 catalyses hydrolysis of C-terminal ubiquityl esters and is involved in recycling ubiquitin ligated to misfolded proteins 
Dominant mutation (I93M) in UCH-L1 identified in one family with inherited PD

Impaired activity of ubiquitin system is KEY for PD pathogenesis

Question 21

Describe the link between DJ-1 in PD

Answer 21

Highly expressed in the brain
Localised to mitochondria and may be important in mitochondrial function. DJ-1 is thought to be a cellular monitor of oxidative stress

Question 22

In summary; what are 3 key genes involved in the pathogenesis of PD?

Answer 22

Alpha synuclein
DJ-1
Parkin

Question 23

Describe the ubiquitin-proteasome system

Answer 23

1. Ubiquitin monomers (Ub) are activated by E1 and transferred to Ub-conjugating enzyme (E2)
2. Proteins are recognized by E3 ligase (parkin) which transfers Ub to a target protein
3. Ub monomers are attached by lysin residue (K) causing poly Ub conjugation
4. Poly Ub chains are linked by K29/K48 signal target proteins for degradation into smaller peptide fragments
5. Poly Ub chains are recyclyed to free monomers by enzymes like UCH-L1.

Question 24

What is the role of LRRK2 in PD pathogenesis?

Answer 24

PARK8 encodes for protein called dardarin
Kinase
One common mutation is G2019S which is a functional mutation which increases kinase activity

Member of MAPK family. In vitro; LRRK2 phosphorylates substrates required for activation of JNK and p38 MAPK

Question 25

What is moesin?

Answer 25

Substrate for mutant LRRK2 Ezrin-radixin-moesin protein family member (stress activated protein kinase family) that regulates neurite outgrowth and the cytoskeleton In hippocampal neurons; mutant LRRK2 interacts with alpha/beta tubulin, a component of the cytoskeleton LRRK2 is involved with cytoskeleton motility and vesicular trafficking which may play a role in PD pathogenesis

Question 26

What are the 2 main hypothesized mechanisms of neurodegeneration in PD?

Answer 26

Misfolding and aggregation of proteins leading to death of SNpc DA neurons Mitochondrial dysfunction and consequently oxidative stress and cell death

Question 27

What evidence is there for the misfolding and aggregation of proteins?

Answer 27

Protein deposition is likely to be toxic to neurons Inherited PD; pathogenic mutations may directly induce abnormal protein conformations (alpha synuclein), or indirectly interfere with processing of misfolded proteins (parkin, UCHL-1) ``` Sporadic; direct protein damaging modifications and indirect changes in processing of misfolded proteins have also been detected Oxidative dress (ROS) is thought to be a possible trigger for dysfunctional protein metabolism ```

Question 28

What is the evidence for mitochondrial dysfunction and oxidative stress?

Answer 28

Defects in oxidative phosphorylation in PD suggested as MPTP blocks mitochondrial electron transport chain by inhibiting complex 1 (NADH dehydrogenase) Abnormalities in mitochondrial complex 1 have been identified in PD

Question 29

Describe the mitochondrial ETC

Answer 29

NADH binds to complex 1 and passes 2 electrons to FMN group FMN is reduced to FMNH2 Electrons are passed to iron sulphur proteins leading to reduction in Fe2+

Question 30

What are the effects of complex 1 (ETC chain) inhibition?

Answer 30

Inhibition of complex 1 increases ROS superoxide This forms a toxic hydroxyl radicals or can react with NO to form peroxynitritie

Question 31

What are the consequences of hydroxyl radical formation or peroxynitrite formation?

Answer 31

Cellular damage by reacting with nucleic acid, proteins and lipids

Question 32

What evidence is there to show that complex 1 inhibition is implicated in the pathogenesis of PD?

Answer 32

Biological markers of oxidative damage are elevated in PD | Content of anti-oxidant glutathione is reduced in PD brains

Question 33

How do cells ultimately die in PD?

Answer 33

In programmed cell death (PCD), intracellular signalling pathways are activated that result in cell death Physiological PCD (apoptosis) is known to be crucial during normal development and as a homeostatic mechanism (e.g. immune system) Dysregulation can contribute to neurodegeneration

Question 34

Is there any evidence for PCD in PD?

Answer 34

Increase in bax-positive staining in the SNpc DA neurons in PD Increased neuronal expression of Bax in PD suggesting that cells are undergoing PCD Other molecular markers are altered in PD including caspase-8, caspase-9 and Bcl-xL This suggested that PCD machinery is activated in postmortem in PD tissue

Question 35

What is Bax?

Answer 35

PCD molecule

Question 36

What toxin based models are used in PD?

Answer 36

6-OH-DA Paraquat Rotenone MPTP

Question 37

What gene based models are used in PD?

Answer 37

Synuclein | Parkin

Question 38

Describe the 6-OH-DA model in PD

Answer 38

1st animal model of PD assoc with SNpc DA cell death 6-OHDA induced toxicity is selective for DAergic neurons (preferential uptake by DA transporter) In neurons; 6-OHDA accumulates in cytosol, generates ROS and inactivates various molecules by generating quinone that attack nucleophilic groups Gradual loss of DAergic neurons will be seen after 6-OH-DA - 80% loss after 6 weeks

Question 39

What are the different types of 6-OH-DA models?

Answer 39

Dependent on the site of injection into the nigrostriatal pathway: a) medial forebrain bundle (MFB): leads to excessive DA depletion b) SNpc: leads to more specific and moderate DA depletions c) sub regions of caudate-putamen (CPu): leads to specific DA depletions Rats with partial lesions of the ventrolateral caudate/putamen are more appropriate models to stufy

Question 40

Describe the pros and cons of the 6-OH-DA model for OD

Answer 40

Pros: Good model for assessing anti-PD actions of new drugs as unilateral striatal lesions causes quantifiable (degree of lesion) asymmetric circling behaviour in animals Cons: Not clear if mechanism of cell death is similar to human PF. 6-OH-DA induced pathology differs from PD (no lewy body formation) Pathology varies depending on injection site of OHDA

Question 41

Describe the MPTP neurotoxin based model of PD

Answer 41

MPTP found to be neurotoxic contaminant In humans and monkeys; MPTP produces irreversible and severe PD syndrome; characterized by tremor, ridigit, slowness of movement, postural instability and freezing Most studies of MPTP performed in monkeys and rodents as only 4 human MPTP cases have come to autopsy

Question 42

Describe the similarities and differences of MPTP to PD

Answer 42

Similarities; low dose MPTP treated monkeys show preferential degeneration of the striatum DA nerve terminals. Regional pattern of MPTP-induced damage is similar to PD (> cell loss in SNpc than VTA; DA neuromelanin-containing cells are more susceptible to damage) Differences; Other monoaminergic neurons (locus coeruleus) are not damaged by MPTP Classical lewy bodies are not found in MPTP humans/ monkeys

Question 43

What is the benefits of a MPTP based model?

Answer 43

Monkey MPTP model is used to assess novel treatments for PD symptoms For example; EP studies reveal hyperactivity of STN as a key factor in PD motor dysfunction: this lead to targeting of STN in DBS procedures to reduce motor function in PD patients Mouse MPTP; enhanced out understanding of mechanisms of DA neurodegeneration

Question 44

Describe MPTP metabolism

Answer 44

1. After systemic administration, MPTP crosses BBB 2. In brain: MPTP is converted to MPDP+ by MAO-B in non-DA cells, then into MPP+ by unknown mechanisms 3. MPP+ released into extracellular space and concentrated into DA neurons via DAT

Question 45

What happens to MPP+ once inside DA neurons?

Answer 45

1. Concentrate in the mitochondria where is blocks complex 1. This results in enhanced ROS production and reduces ATP synthesis (toxic) 2. Interacts with cytosolic enzymes (toxic) 3. Sequesters into synaptic vesicles via vesicular monoamine transporter (VGAT)

Question 46

Describe the paraquat (pesticide) based model for PD

Answer 46

Herbicide that induces a toxin-model of PD Similar structure to MPP+ Exposure to paraquat increases risk of PD Does not easily cross BBB; instead, toxicity is due to superoxide radial formation Systemic administration in mice leads to SNpc neuro-degeneration and alpha synuclein containing inclusions

Question 47

Describe the pros and cons of paraquat PD models

Answer 47

Pros: Useful to study role of alpha-synuclein in neurodegeneration (reliably causes DA cell loss and alpha synuclein positive inclusions) Cons: Not known if DA toxicity is selective or other neurons are affected

Question 48

What is the difference between paraquat and MPP+?

Answer 48

Paraquat has an N-methyl-pyridinium group whereas MPP+ has a phenyl group

Question 49

Describe the use of rotenone as a model for PD

Answer 49

Member of rotenoid family of cytotoxic compounds Insecticide and fish poison Highly lipophilic; gains access to most organs Binds to the same site as MPP+ on the mitochondria to inhibit complex 1 of ETC IV rotenone in rats; selective degeneration of DA neurons and alpha synuclein positive inclusions Rotenone-treated rodents develop abnormal posture and slowness of movement

Question 50

Describe the pros and cons of rotenone as a PD model

Answer 50

Pros: Good model for studying relationship between aggregate formation and cell death Cons: Rotenone has widespread neurotoxic actions; not DA selective

Question 51

Describe the theory of genetic models in PD

Answer 51

Discovery of PD genes has allowed the generation of specific genetic models with specific significance to PD Expectation is that genetic and sporadic forms of PD share similar pathogenic mechanisms Studies in genetic models focus research on key biochemical pathways All PD genes (alpha synuclein, parkin, UHCL-L1) influence ubiquitin protein, degradation of proteins or influence on mitochondrial function

Question 52

Describe the alpha synuclein model of PD

Answer 52

Mice overexpress normal or mutated alpha synuclein Severity of phenotypes depends on promotor used to make transgene Overexpression of alpha synuclein in WT; neurochemical deficits in nigrostriatal pathway, behavioural abnormalities, alpha synuclein accumulation Mice also show accelerated age related loss in neurons

Question 53

Describe the parkin mouse model in PD

Answer 53

Loss of function of parkin (E3 ligase); most are recessive. Most models focus on parkin -/- mice

Question 54

Describe a quaking mouse mutant (parkin PD model)

Answer 54

Spontaneous deletion of parkin. Mice have myelin deficiency and enhanced DA metabolism Mice display behavioural deficits and tremor in the trunk region and extremities

Question 55

Describe the parkin k/o mouse (defective exon 3) in the parkin PD mouse model

Answer 55

Mice have progressive motor anomalies and deficits in sensorimotor integration Paradoxically, mice have an increased basal release of DA and reduced striatal neuronal excitability

Question 56

Summarize the genetic mouse models in PD

Answer 56

Both alpha synuclein overexpress mice and parkin -/- mice do not reproduce the full spectrum of anomalies found in humans. In particular, specific loss of nigrostriatal DA neurons The models however show clear sensorimotor anomalies Parkin -/- mice show reduced levels of proteins involved in mitochondrial function and oxidative stress Models offer the chance to elucidate ea`rly changed caused by parkin mutations that lead to neurodegeneration

Question 57

Where is large DA found?

Answer 57

Corpus striatum Limbic system Hypothalamus

Question 58

How is DA synthesized?

Answer 58

Catecholamine Synthesis: Tyrosine to dopa via tyrosine hydroxylase activity followed by decarboxylation to form DA DA can then be further broken down to adrenaline and NA by dopamine beta hydroxylase

Question 59

How is DA uptaken and metabolised?

Answer 59

DA taken up by a specific DA transporter Metabolised by MAO-B and COMT to form: DOPAC HVA

Question 60

What are the different dopamine receptors?

Answer 60

``` D1 class (D1 and D5): stimulated adenylyl cyclase and cAMP D2 class (D2,3,4): inhibit adenylyl cyclase; reduce cAMP ```

Question 61

Where are DR receptors distributed?

Answer 61

D1,5; brain and smooth muscle. Mostly post-synaptic inhibition D2,3,4; brain, CV, presynaptic nerve terminals. Pre and post synaptic inhibition Only D2 and D3 are expressed presynaptically Regulation of DA release is modulated principally by D3 autoreceptors Regulation of DA biosynthesis and metabolism is mediated by D2

Question 62

Describe the DA pathways within the brain

Answer 62

Nigrostriatal; motor control (SNpc (midbrain) to corpus striatum) Mesolimbic cortical: emotion and reward (VTA (midbrain) to limbic system, cerebral cortex and striatum) Tuberohypophysial: endocrine control (Arcuate nucleus of periventricular area (hypothalamus) to infundibulum, anterior pituitary)

Question 63

How is motor processed in the BG?

Answer 63

Balance between direct (nigral-striatal) and indirect (striatal-pallidal) Inhibitory influence of direct pathway on BG output (SNr/ GPi) is counterbalanced by the disinhibitory influence of the indirect pathway

Question 64

Describe the receptors involved within the direct pathway of BG

Answer 64

Dynorphin containing medium spiny neurons | DA acts at D1 receptors to excite dynorphin containing medium spiny neurons

Question 65

Describe the receptors involved with the indirect pathway of BG

Answer 65

In striatum, DA acts on postsynaptic D2 receptors expressed on enkephalin containing striatal pallidal neurons, resulting in their inhibition

Question 66

What goes wrong in PD at the BG level?

Answer 66

Lack of DA causes reduced activation of striatal D1 and D2 receptors. This results in : Reduce inhibition in indirect pathway Decreased excitation in direct pathway Net result: excessive activation of GPi-SNr complex and over inhibition of thalamocortical centres

Question 67

What are the current pharmacological therapies to treat PD?

Answer 67

``` Increase production of endogenous DA Drugs that mimic DA action Drugs that prevent degradation of endogenous (MAOB) or exogenous DA (COMT) Drugs that release dopamine Muscarinic cholinergic antagonists ```

Question 68

Describe levodopa

Answer 68

1st line: DA precursor that crosses BBB Combined with dopa decarboxylase inhibitor (e.g. carbidopa) to reduce dose required and reduce peripheral side effects In periphery; decarboxylase inhibitor prevents levodopa conversion to DA In brain: decarboxylase Is do not penetrate BBB and decarboxylation occurs rapidly

Question 69

Describe the kinetic aspects of levodopa

Answer 69

Well absorbed by small intestine via active transport At start of treatment; 80% patients show improved function with 20% showing complete cure BUT effectiveness of levodopa gradually declines This is due to: Natural progression of disease Receptor downregulation

Question 70

What are some acute side effects of levodopa

Answer 70

Nausea and anorexia Hypotension Psychological: hallucinations, delusions (schizophrenic like symptoms due to increased DA within mesolimbic pathway) Slowly developing as PD progresses: dyskinesia, on/off effect

Question 71

How can the long term side effects of levodopa be counteracted?

Answer 71

Animal models and clinical studies indicate more effective control with a continuous supply of DA E.g. MPTP treated primates show reduced motor complications if treatment involved a long acting DA agonist rather than short acting Continuous infusion devices however are very impractical for PD patients

Question 72

Describe the action of selegiline (MAO-B Inhibitor)

Answer 72

MAO inhibitor - selective for MAO-B which predominates in DA containing regions DA levels are increased as metabolism of DA is blocked Lacks unwanted peripheral SE of non-selective MAO Is MAO-B inhibition protects DA from intraneuronal degradation

Question 73

Describe DA receptor agonists

Answer 73

Selective D2 agonists produce consistent anti-parkinsonism effects whereas D1 receptors may produce a broader rage of effects Bromocriptine (potent D2R); longer duration of action (half life is 6-8hrs) Apomorphine (s/c via continuous pump) Lisuride Pergolide (D1/2 agonist) SE: similar to levodopa; limits doses that can be used

Question 74

Describe the role of muscarinic antagonists in PD

Answer 74

Normally, the cholinergic system in the striatum is restrained by the DAergic pathway Antagonise the action of ACh to limit this activity to makeup for a lack of DA

Question 75

Describe the role for adenosine A2A receptor antagonists in PD

Answer 75

Adenosine A2A receptors have a very restricted expression in the CNS; enriched in the striatum High levels are expressed on D2 receptors (enkephalin) expressing GABAergic striatal neurons Studies have shown functional interactions between A2A and D2 receptors E.g. activation of A2ARs opposes the effects of D2rs by decreasing the affinity for DA D2Rs activating signalling cascades that D2Rs inhibit Consequently, A2AR antagonists would be expected to enhance effects of DA on striatal neurons Blocking A2ARs should partially reinstate the thalamocortical motor stimulatory activity

Question 76

Why is the use of mAChR limited?

Answer 76

Thy reduce tremor more than rigidity/ hypokinesia Troublesome SE; dry mouth, constipation, impaired vision, urinary retention Mainly used for parkinsonism induced by antipsychotics

Question 77

Is there any experimental evidence for anti-parkinsonian action of A2ARs?

Answer 77

A2AR antagonists increase basal locomotion in rats In a hypoDAergic rodent model of motor function induced by haloperidol; A2AR antagonist reverses haloperidol induced catalepsy A2AR blockage improves abnormal muscle tone and tremor in PD models A2A antagonists completely reverses tremulous jaw movements and haloperidol induced catalepsy

Question 78

What are the neuroprotective actions of A2A antagonists?

Answer 78

Coffee/ tea drinking (caffeine intake): assoc with reduced risk of PD in humans (caffeine = AR antagonist) In rodent models; caffeine and other selective A2A antagonists protect against DA neuronal toxicity Mice given caffeine display dose-dependent reversal of MPTP induced loss of nigrostriatal DAergic neuros

Question 79

What are the side effects of A2AR antagonists?

Answer 79

Pro-inflammatory Ischaemic tissue damage (cardiac, renal, hepatic) Psychosis Insomnia

Question 80

Describe the role of neural transplantation in PD

Answer 80

As PD results from the selective loss of SNpc DA neurons | Injection of dissociated foetal cells into the SNc

Question 81

What are the pros and cons of stem cells for neural transplantation in PD?

Answer 81

Very promising Stem cells can be induced to become DA neurons and in theory could completely replace DA neuron loss Cons; tumour formation, tissue rejection

Question 82

Can stem cells be used or neural transplantation in place of foetal tissue?

Answer 82

Embryonic stem cells (ESC); can differentiate into neurons | Induce pluripotent stem cells (iPSC); adult stem cells that can differentiate into DA neurons specifically

Question 83

Describe the role of deep brain stimulation in PD

Answer 83

Increasingly accepted as an adjunct therapy for PD Surgical treatment; intractable tremor, long term complications of L-dopa Subthalamic nucleus and GPi are targeted; with studies to show that STN stimulation is superior to GPi as it produces a more pronounced anti-akinetic response

Question 84

Describe how STN stimulation works to mitigate PD symptoms

Answer 84

STN controls the output nuclei of the basal ganglia (GPi, SNr) STN recieves input from GPe and cortex, perifascicular nucleus of thalamus and PPN

Question 85

Are there any other surgical procedures utilised in PD?

Answer 85

Lesioning; thalamotomy, pallidotomy, subthalamotory ``` Pallidotomy is more common type and targets the GPi leading to relief of: Tremor Rigidity Bradykinesia Motor fluctuations Dyskinesia ```

Question 86

Has gene therapy been utilised in PD?

Answer 86

Less than invasive; may halt progression of PD Technique uses viral vectors to introduce a protein of interest (neuroprotective or neurorestorative) into a specific brain region

Question 87

How do viral vectors reach the brain?

Answer 87

Port into the subthalamic nuclei. The virus delivers a gene that prompts the cell to produce GAD GAD (glutamate decarboxylase) is the key enzyme that synthesizes GABA

Question 88

Why is GAD the gene therapy of choice in PD?

Answer 88

Forms GABA In PD: STN is disinhibited resulting in pathological excitation of its targets (GPi and SNpr) In turn; increased GPi/ SNpr outflow is though to underlie tremor, rigidity and bradykinesia Therefore, increased GABA in STN will alleviate this by inhibiting STN activity

Question 89

Is there evidence that GAD gene therapy works?

Answer 89

PD patients are currently taking part in clinical trials o deliver GAD to STN; currently no serious adverse effects but only a small no. patients have been studies

Question 90

What is another protein (not GAD) targeted in PD gene therapy?

Answer 90

GDNF; growth factor that promotes DA survival and regeneration in rodent and primate PD models Several methods of GDNF delivery have proven to prevent the loss of DA neurons in animal models of PD Human cases; success is variable.

Question 91

What are the potential problems with gene therapy?

Answer 91

Short term results; patients must undergo treatment every few months Immunological; immune system can identify and destroy the viral vector Toxicity; viral vector may mutate and become pathogenic