PARK Genes Link Mitochondrial Dysfunction and Alpha-Synuclein Pathology in Sporadic Parkinson’s Disease

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.

MUTATION ANALYSIS OF DJ-1 GENE IN VIETNAMESE PARKINSON’S DISEASE PATIENTS

Parkinson’s disease (PD) is a degenerative condition of the brain of uncertain cause that mainly affects older people. Shaking is a distinctive feature of the disease, but slowness, poverty of movement and stiffness interfere with everyday life. A large number of known pathogenic mutations of genes related to PD have been identified. The DJ-1 gene, one of PARK genes, is considered as the primary cause of PD in different populations. The analysis of mutation frequency of the DJ-1 gene in Vietnamese PD patients is necessary to clarify the pathogenic associations of PD with the DJ-1 gene and to understand the pathogenesis and genetic mechanisms of PD. In this study, genomic DNA was extracted from peripheral blood of 30 PD patients (mean age 64.11 ± 7.31 years) and 20 controls and directed Sanger sequencing of one fragment of DJ-1 gene, containing the introns 4 and 5 as well as exon 5. The obtained results showed that there were 13 heterozygous or homozygous point mutations in introns 4 and 5. The late-onset sporadic PD (LOPD) patient carried a single homozygous mutation in intron 5 (IVS5+31G>A), and others had a heterozygous mutation, all of unknown significance. Moreover, both the Ala86Glu and Gly95Leu mutations in exon 5 were present in one LOPD patient suggesting possible change of functional protein. Analysis of these mutations were shown the nonsynonymous and uncertain significant mutation, therefore they may not be related to pathogenic mutations of PD. Further research is needed to study the contribution of the novel found mutation in other PARK genes to the pathogenesis of Vietnamese PD patients.

The importance of Wnt signalling for neurodegeneration in Parkinson's disease

PD (Parkinson's disease) is a devastating progressive motor disorder with no available cure. Over the last two decades, an increasing number of genetic defects have been found that cause familial and idiopathic forms of PD. In parallel, the importance of Wnt signalling pathways for the healthy functioning of the adult brain and the dysregulation of these pathways in neurodegenerative disease has become apparent. Cell biological functions disrupted in PD are partially controlled by Wnt signalling pathways and proteins encoded by PARK genes have been shown to modify Wnt signalling. This suggests the prospect of targeting Wnt signalling pathways to modify PD progression.