Parkinson's Disease Mechanisms

Question 1

Autosomal Dominant mutations

Answer 1

SNCA, VPS35, LRRK2, UCHL1

Question 2

AR mutations

Answer 2

PINK1, Parkin, Drp1, ATP132A

Question 3

Genetic Risk Factors

Answer 3

GBA

Question 4

Describe mitochondrial fusion and fission

Answer 4

The IMM and OMM are cleaved by Drp1 which is recruited to the membrane via Mffn, Mid49 and Mid51. Following which fusion of the OMM is aided by Mfn1/2 and IMM is mediated by OPA1

Question 5

Why are fusion and fission so neccessary - whats the evidence?

Answer 5

To maintain a pool of functional mitochondria following cellular stress, in particular environmental and metabolic

Question 6

Discuss PARK2 mutations

Answer 6

Encodes parkin, a E3 ubiquitin ligase like enzyme. It is present in around 50% of familial cases, and less than 1% of sporadic. It presents with no lewy bodies, hyper-reflexia and dystonia. Additionally it has an early age of onset (less than 40)

Question 7

What is the effect of a PARK2 mutation?

Answer 7

Main defects are respiratory chain and mitochondrial defects. It is implicated in mitochondrial turnover and function. Park2 mutations are a loss of function mutations, and knockout mice have demonstrated dsyfunciton of the SN - this could be owed to the SNs indirect susceptibility to mitochondrial defects thanks to the high levels of OS implicated in L-Dopa metabolism.

Question 8

What are the neuorprotective features of PARK2

Answer 8

Parkin decreases apoptosis, KO proved mice more susceptible to apoptosis. It does so through binding to the depolarised membrane of dsyfunctional mitochondria and initiating mitophagy through the ubiquitination of membrane proteins e.g. Mfn1/2, however this has since been disputed (NVM). In doing so it prevents the release of pro-apoptic factors e.g. Bax and BcI2

Question 9

Discuss PARK6 Mutations

Answer 9

PTEN Induced Kinase 1. 20 mutations have been identified, and thought to cause around 10% of early onset (»1%). Presents with atypical features, such as psychiatric symptoms, no pathological lewy bodies present upon autopsy and gait problems. Additionally the protein is thought to be a serine/threonine kinases and it has been argued to interact with parkin.

Question 10

Discuss PINK1 mutations

Answer 10

Promotes cell surivival in times of oxidative stress. KO show extreme mito dsyfunction and fragmentation.

Question 11

Describe the role of PINK1 and parkin during mitophagy?

Answer 11

PINK1 is recruited to the mitochondrial membrane following depolarisation, it subsequently ubiquitinates and phosphorylates membrane proteins and recruits parkin through phosphorylation. The process results in the formation of the autophagosome which downstream results in mitophagy.

Question 12

Discuss LRRK2 Mutations

Answer 12

A variety of mutations have been identified in both sporadic and familial. Thought to present in 2% of the PD population (35% in the Ashkenazi and N.American Population). The most common mutation is G2019S.

Question 13

VPS35

Answer 13

Vacuolar Protein Sorting-Associated Protein 1. M6P bind lysosomal enzymes following processing in the golgi and traffic to lyosoomes, following this they must be brought back to the golgi with the aid of the retromer complex, composed largely of VPS35. Mutations, the missesnse D620N stop this process from happening. General disruption to macroautophagy - huge disruptions to proteostasis.

Question 14

Dj-1

Answer 14

Extremely rare cause of early onset.
Its native role is unknown, could be in the maintenaince of oxstress as it is seen to be upregulated following ROS generation.

Question 15

ATP132A

Answer 15

Early onset, typically found localised in lyososmal membrane. Type 5 P-type ATPase involved with Zn2+ transport into lysosomes. Affects lysosomal function leading to impaired protein degradation. May also lead to Zn2+ dysregulation affecting mitochondria and endosomal functions.

Question 16

GBA

Answer 16

Is a risk factor.
UK -4.2% of PD patients have it, whilst in Ashenkazi Jews 31% have it
N370S and L44P are the most common mutations in PD - which is strange as N370S is implicated in mild gauchers. 80% of PD carriers dont go on to develop parkinsons. This is suggestive of more environmental effects playing a role. in PD etiology. Glucosecerebrodase is a lysosomal enzyme that is involved in the breakdown of glucocerebroside to glucose and ceramine. There is a build up of glucocerebroside in lyosomes, this has been implicated in pathology.

Question 17

How has the role of parkin recently been relegated?

Answer 17

Youle’s lab now adds a loop-the-loop to the linear pathway mitophagy pathway, which relegates parkin to the role of optional player (Lazarou et al. 2015). When it’s there, parkin does ubiquitinate mitochondrial proteins that then act as substrates for PINK1. But it is not necessary. PINK1 can also start mitophagy all by itself. In the latter case, the occasional ubiquitination of mitochondrial proteins, due to natural protein turnover, provides enough substrate for PINK1 to phosphorylate and get mitophagygoing.

Question 18

What is ceremide required for?

Answer 18

Lipid biosynthesis - this leads to altered lipid profiles, much like the decreased in PUfs seen in PD. What is interesting is that PUfs were determined to dock Asyn oligomers onn the membrane, preventing aggregation, as their numbers decrease fibril formation increases - could explain age dependent behaviour, or why GBA encourages early onset

Question 19

What are the mutations that effect lysosomal function

Answer 19

GBA - no reaction, build up of GC, decreased lysosomal function
ATP132A - lysosomal protein
VPS35 - retromer, M6P

Question 20

UPS defects in PD

Answer 20

Parkin is an E3 ligase

UCHL1 - involved in ub recycling

Question 21

CMA defects in PD

Answer 21

Asyn usually degraded by CMA

Lysosomal dsyfunction could lead to increased synuclein levels