Parkinson's disease

PINK1 and PARKIN form a critical signaling pathway for maintaining mitochondrial health. PINK1, a resident mitochondrial protein kinase, senses mitochondrial dysfunction. When the mitochondrial membrane potential drops due to damage, PINK1 accumulates on the outer mitochondrial membrane (OMM). This accumulation signals PARKIN, an E3 ubiquitin ligase residing in the cytosol, to translocate to the OMM. Once there, it promotes mitophagy, the selective autophagic degradation of dysfunctional mitochondria. This targeted degradation allows the removal of damaged organelles while preserving the integrity of the remaining mitochondrial network, ensuring efficient energy metabolism.

DJ-1 is critical in cellular protection against oxidative stress. It regulates both transcription and signal transduction pathways, orchestrating cellular responses. DJ-1 acts as a free radical scavenger, neutralizing reactive oxygen species that can damage cellular components. DJ-1 primarily resides in the cytoplasm but translocates to the OMM upon oxidative stress, interacting with mitochondrial proteins.

Mutations in DJ-1 may disrupt complex I-dependent mitochondrial respiration, potentially impacting energy production. Evidence suggests interplay between DJ-1, PINK1, and PARKIN in maintaining mitochondrial health. In vitro models of PD show that DJ-1 can interact with PINK1, forming a complex that protects cells against oxidative stress. Similarly, PARKIN also relocates to the OMM under oxidative stress conditions. Further investigation is needed to confirm whether this interplay between DJ-1, PINK1, and PARKIN occurs in vivo and to elucidate its significance in the development of PD.

Alpha-synuclein (α-syn) has several functions in dopaminergic neurons. Notably, α-syn downregulates protein kinase C, protecting cells against apoptosis. Additionally, it acts as a chaperone within a heat shock protein complex, crucial for maintaining protein conformation and facilitating the refolding or degradation of misfolded proteins.

In PD, abnormal aggregates of α-syn form Lewy bodies and Lewy neurites, a hallmark pathology. These pathogenic α-syn aggregates, alongside mitochondrial dysfunction, are considered key contributors to PD onset. Interestingly, mutations in the SNCA gene can influence both α-syn expression and the risk of developing autosomal dominant PD.

Studies on post-mortem PD brain tissue revealed α-syn accumulation can impair the mitochondrial membrane. Its presence disrupts mitochondrial morphology, leading to fragmentation, potentially triggering mitophagy (mitochondrial degradation) and nitrosative stress. Furthermore, α-syn can impede the import of essential mitochondrial proteins.

α-syn can localize to various mitochondrial compartments – the outer and inner membranes, the intermembrane space, and the matrix – in response to cellular cues. Through its C-terminal region, α-syn directly interacts with mitochondrial proteins, affecting several crucial functions that influence mitochondrial biogenesis, dynamics, and transport. Notably, wild-type α-syn can even repress mitophagy mediated by PINK1 and PARKIN, potentially by reducing PARKIN recruitment to mitochondria. Taken together, α-syn mutations impact numerous aspects of mitochondrial function, ultimately contributing to the pathogenesis of PD.

LRRK2 mutations significantly contribute to PD, accounting for approximately 1% of sporadic and 4% of familial cases. The protein encoded by LRRK2 exhibits intricate regulation through its GTPase and kinase domains. LRRK2 undergoes autophosphorylation, suggesting a potential role for kinase activity in modulating GTPase function. Notably, LRRK2-induced neuronal toxicity is directly linked to its kinase activity. Most pathogenic mutations enhance kinase activity via domain-specific mechanisms. However, the precise cause-and-effect relationship between LRRK2 dysfunction and PD development remains under active investigation, with LRRK2 transgenic mouse models yielding conflicting results.

Intracellularly, LRRK2 localizes to several vesicular components like the ER-Golgi, endolysosomes, and multivesicular bodies. By doing so, it functions as a scaffold for protein-protein interactions through its repeat regions and directly modulates key signaling pathways, including WNT, MAPKKKs, PKA, MAPK, β-catenin, disheveled, and LRP6, through its kinase activity.

Through these signaling pathways, LRRK2 influences a broad spectrum of cellular processes, including protein translation, cytoskeletal organization, endolysosomal vesicular sorting and trafficking (involving the trans-Golgi network and other organelles), multiple types of autophagy (including macroautophagy and mitophagy), interactions with bacterial pathogens, and regulation of lysosomal homeostasis.

Understanding the interplay between mitochondrial dysfunction and protein abnormalities like those caused by PINK1, PARKIN, DJ-1, and α-syn is crucial for developing effective therapeutic strategies for PD. While the precise mechanisms remain under investigation, these proteins play a complex and interconnected role in maintaining mitochondrial health in dopaminergic neurons. Further research on these pathways holds promise for identifying potential targets for neuroprotection and ultimately slowing or preventing the progression of PD.