Abstract
Parkinson’s disease (PD) is an age-related neurodegenerative disorder affecting millions of people worldwide. The disease is characterized by the progressive loss of dopaminergic neurons and spread of Lewy pathology (α-synuclein aggregates) in the brain but the pathogenesis remains elusive. PD presents substantial clinical and genetic variability. Although its complex etiology and pathogenesis has hampered the breakthrough in targeting disease modification, recent genetic tools advanced our approaches. As such, mitochondrial dysfunction has been identified as a major pathogenic hub for both familial and sporadic PD. In this review, we summarize the effect of mutations in 11 PARK genes (SNCA, PRKN, PINK1, DJ-1, LRRK2, ATP13A2, PLA2G6, FBXO7, VPS35, CHCHD2, and VPS13C) on mitochondrial function as well as their relevance in the formation of Lewy pathology. Overall, these genes play key roles in mitochondrial homeostatic control (biogenesis and mitophagy) and functions (e.g., energy production and oxidative stress), which may crosstalk with the autophagy pathway, induce proinflammatory immune responses, and increase oxidative stress that facilitate the aggregation of α-synuclein. Thus, rectifying mitochondrial dysregulation represents a promising therapeutic approach for neuroprotection in PD.
Highlights
Parkinson’s disease (PD) is an age-related neurodegenerative disorder with an insidious onset and a substantial preclinical phase
Information for SNCA, Leucine-Rich Repeat Kinase 2 (LRRK2), Vacuolar Protein Sorting 35 Ortholog (VPS35), PRKN, PTEN Induced Kinase 1 (PINK1), DJ1, ATP13A2, PLA2G6, F-Box Protein 7 (FBXO7), and VPS13C in this table were extracted from MDS gene, International Parkinson and Movement Disorder Society
Mouse models studying G2019S, R1441G, and Lrrk2-deficient failed to show correlation between loss of function (LOF) of LRRK2 and αsynuclein pathology (Daher et al, 2012; Xiong et al, 2017) but impaired parkin-mediated mitophagy is found in fibroblasts from patients with the G2019S mutation (Bonello et al, 2019)
Summary
Parkinson’s disease (PD) is an age-related neurodegenerative disorder with an insidious onset and a substantial preclinical phase (estimated as >20 years). Dt,CA4, ATZ, BMA, Bradykinesia; CgGr, Rigidity; Dystonia; SN,10, Tremor at rest CgGf, CA2, BMA, Dt, SPL, Acb, Pu, VTA, RaM, FuG, STG RPN, Yes
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