PINK1 – Parkinson Disease

PINK1 (PTEN-induced putative kinase 1) is definitively associated with autosomal recessive Parkinson disease, typically presenting as early-onset, levodopa-responsive parkinsonism with slow progression and frequent motor fluctuations. Patients harbor homozygous or compound heterozygous loss-of-function mutations in PINK1, leading to impaired mitochondrial quality control and dopaminergic neuron degeneration. Clinical features often overlap idiopathic PD but include earlier age at onset (mean ~32 y) and prominent psychiatric or cognitive symptoms in some families (PMID:20356854).

Genetic evidence spans dozens of unrelated probands across multiple populations. Autosomal recessive inheritance is supported by segregation of pathogenic variants in at least 19 additional affected relatives in large pedigrees (PMID:25226871). Case series describe over 17 homozygous or compound heterozygous carriers of nonsense, missense, splice-site, and frameshift mutations, including the recurrent c.1366C>T (p.Gln456Ter) and c.1488+1G>A splice-donor variants. The variant spectrum encompasses missense (e.g., p.Pro209Ala), nonsense (p.Trp437Ter), and LoF alleles with founder effects in specific ethnic groups (PMID:23063710).

Experimental studies demonstrate that PINK1 deficiency disrupts mitochondrial membrane potential, increases oxidative stress, and triggers apoptotic cascades in neuronal models. Wild-type PINK1 prevents cytochrome c release and caspase 3 activation under basal and stress conditions, a protection lost in kinase-dead or disease-associated mutants (PMID:16079129). Drosophila Pink1 knock‐out replicates muscle degeneration and dopaminergic neuron loss, which is rescued by Parkin overexpression, confirming a conserved PINK1–Parkin pathway in mitochondrial homeostasis (PMID:16818890).

Conflicting data on heterozygous carriers suggest subtle dopaminergic dysfunction and mild hypokinesia but do not refute the recessive inheritance model. No strong evidence disputes PINK1’s role in early-onset parkinsonism.

Overall, over 45 unrelated patients from >20 pedigrees with concordant functional assays and animal models establish a definitive gene–disease relationship. PINK1 genetic testing is recommended in cases of early-onset Parkinson disease, especially with autosomal recessive inheritance or atypical features. Functional assays of novel variants should include mitochondrial import and kinase activity studies.

Key take-home: PINK1 loss-of-function mutations cause autosomal recessive early-onset Parkinson disease via mitochondrial dysfunction; genetic testing informs diagnosis, prognosis, and personalized management.

References

• Archives of neurology • 2004 • Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease. PMID:15596610
• Brain • 2010 • PINK1-linked parkinsonism is associated with Lewy body pathology. PMID:20356854
• Parkinsonism & related disorders • 2014 • Early-onset Parkinson's disease due to PINK1 p.Q456X mutation—clinical and functional study. PMID:25226871
• Mitochondrion • 2013 • PINK1 parkinsonism and Parkinson disease: distinguishable brain mitochondrial function and metabolomics. PMID:23063710
• The Journal of biological chemistry • 2005 • Wild-type PINK1 prevents basal and induced neuronal apoptosis, a protective effect abrogated by Parkinson disease-related mutations. PMID:16079129
• Proceedings of the National Academy of Sciences of the United States of America • 2006 • Mitochondrial pathology and muscle and dopaminergic neuron degeneration caused by inactivation of Drosophila Pink1 is rescued by Parkin. PMID:16818890

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