Pathogenesis of Parkinson's Disease
Parkinson's Disease (PD) is linked to both environmental & genetic factors.
Environment factors: Many PD cases are due to the environment. Exposure to Pesticides can lead to Parkinson’s disease. Also, exposure to drugs such as cocaine, marijuana, etc. may also lead to PD. The drugs cause overstimulation of dopaminergic neurons, leading to alpha synuclein aggregation and loss of neuronal functions leading to PD.
Genetic factors: Several genes have been identified in PD. The causative mutations of PD are rare, while the ones predisposing to it are more common. Some genes that have been linked to PD are:
1) SNCA gene (that codes for Alpha-Synuclein)
2) GBA gene
3) BNIP-3L
4) PARK 2 (PARKIN) & PINK-1 (PTEN Induced Kinase 1) mutations
1) SNCA gene mutation
Missense mutations of SNCA gene may promote misfolding of the alpha synuclein protein and some of them are directly linked to Parkinson’s disease. There are several missense mutations linked to PDs. Alpha synuclein's role is not very well-known, but it's thought to be involved in neurotransmission. It forms a complex with SNARE protein & helps neurotransmitters (in particular dopamine) to be secreted. So, when there is a loss of functions of alpha synuclein, we can have 2 problems:
1) Alpha synuclein aggregation & neuronal death.
2) Neuroinflammation that occurs after the neuronal death.
2) GBA mutation in PD
The GBA gene encodes the enzyme glucocerebrosidase, which breaks down a fatty substance called glucocerebroside. Mutations in the GBA gene are associated with Gaucher disease, a disorder characterized by the build-up of glucocerebroside in various organs and tissues. Especially in heterozygous state, GBA mutation may predispose to Parkinson’s. 25% of Parkinson’s patients have this variant in heterozygous state. (Heterozygous means one mutated allele is present, homozygous means 2 mutated alleles are present. GBA mutations in homozygous states are rare). When the cause of PD is GBA, some drugs (enzyme replacement therapy) can replace GBA. Also, gene therapy could be tried.
3) BNIP-3L mutation
BNIP3L (also known as NIX) is a protein involved in the process of mitophagy in various cell types including neurons. (Mitophagy is the selective degradation of damaged/dysfunctional mitochondria. Mitophagy is crucial for mitochondrial health and function, which is crucial for neuronal survival). According to studies, BNIP3L/NIX localize to damaged mitochondria & promote their engulfment by autophagosomes, leading to their degradation. Dysfunction in BNIP3L may disturb BNIP3L mediated mitophagy process, thus contributing to the accumulation of damaged mitochondria & neuronal degeneration.
4) PINK1 Or PARK2 mutations
Mutation of Park2 gene & PINK1 gene are linked to Parkinson’s disease. PARKIN & PINK1 proteins are involved in PINK1-PARKIN mediated mitophagy of damaged mitochondria.
PARKIN is a protein encoded by the PARK2 gene. PARKIN is E3 Ubiquitin Ligase (the 3rd enzyme in the Ubiquitination process.) It has an important role in ubiquitination, a cellular pathway responsible for degrading and recycling damaged protein. PARKIN labels target proteins/molecules with Ubiquitin (Ub), thus, directing them towards degradation in proteasomes & lysosomes.
PINK1 (PTEN-induced kinase 1) is a mitochondrial kinase encoded by the PINK1 gene. PINK1 is a mitochondrial quality control sensor whose function is to maintain mitochondrial health & protect cells from mitochondrial dysfunction.
Process of PINK1-PARKIN mediated mitophagy
When mitochondria depolarizes (mitochondrial membrane potential drops due to mitochondrial damage), PINK1 is activated, PINK1 recruits PARKIN to damaged mitochondria , PARKIN (a E3 ubiquitin ligase) helps “Ubiquitin” to attach to mitochondrial proteins. A heavily ubiquitinated mitochondrial surface proteins signals its degradation/destruction. Thus, PINK1 & PARKIN induce mitophagy (autophagy of damaged mitochondria). Thus this prevents the accumulation of dysfunctional mitochondria in the cell & ensures their removal.
If PINK1 or PARK2 gene is mutated, their protein products are dysfunctional mitophagy is inhibited, dysfunctional mitochondria accumulates & leads to the death of the cells in which PINK1 and PARK2 are essential (e.g., dopaminergic neurons). So, in both cases, mutation in PINK1 (loss of function), or mutation in PARK2 (loss of function) leads to destruction of dopaminergic neurons, causing Parkinson phenotype. So, mutation of PINK1 or PARK2 causes Parkinson disease due to the loss of dopaminergic neurons. (not due to alpha-synuclein). (In this PD case, we may not find synuclein in dopaminergic neurons, after the autopsy of this subject because PD in this case is not related to Alpha Synuclein, but to the loss of the dopaminergic neurons due to mechanisms different from Alpha synuclein).
So, When we approach a ND disorder, we need to remember that “In NDDs, different genes are involved & their mutations may lead to loss of the same kind of neurons giving a specific phenotype. Also, other gene mutations may lead to accumulation of specific proteins leading to the loss of the same kind of neurons and thus, giving the same phenotype”. So, If we see that dopaminergic neurons in substantia nigra are lost & the phenotype is same as PD, we can define it as PD (although the pathogenesis leading to the neuronal death may be different).