Parkinson's Disease Mechanisms Flashcards
Autosomal Dominant mutations
SNCA, VPS35, LRRK2, UCHL1
AR mutations
PINK1, Parkin, Drp1, ATP132A
Genetic Risk Factors
GBA
Describe mitochondrial fusion and fission
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
Why are fusion and fission so neccessary - whats the evidence?
To maintain a pool of functional mitochondria following cellular stress, in particular environmental and metabolic
Discuss PARK2 mutations
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)
What is the effect of a PARK2 mutation?
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.
What are the neuorprotective features of PARK2
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
Discuss PARK6 Mutations
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.
Discuss PINK1 mutations
Promotes cell surivival in times of oxidative stress. KO show extreme mito dsyfunction and fragmentation.
Describe the role of PINK1 and parkin during mitophagy?
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.
Discuss LRRK2 Mutations
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.
VPS35
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.
Dj-1
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.
ATP132A
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.
GBA
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.
How has the role of parkin recently been relegated?
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.
What is ceremide required for?
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
What are the mutations that effect lysosomal function
GBA - no reaction, build up of GC, decreased lysosomal function
ATP132A - lysosomal protein
VPS35 - retromer, M6P
UPS defects in PD
Parkin is an E3 ligase
UCHL1 - involved in ub recycling
CMA defects in PD
Asyn usually degraded by CMA
Lysosomal dsyfunction could lead to increased synuclein levels
