PINK1 – autosomal recessive early-onset Parkinson disease 6

PINK1 has been causally linked to autosomal recessive early-onset Parkinson disease 6 (PARK6), a rare form of parkinsonism with juvenile onset and slow progression. PARK6 follows an autosomal recessive inheritance pattern with biallelic loss-of-function or missense mutations in PINK1.

Genetic evidence for the PINK1–PARK6 association includes six unrelated probands harboring recessive biallelic PINK1 mutations identified through linkage in consanguineous families (PMID:15349870). Segregation analyses in these pedigrees confirm co-segregation of homozygous or compound heterozygous variants with early-onset parkinsonism.

The variant spectrum in PARK6 comprises truncating (nonsense and frameshift) and missense alleles across the kinase domain and C-terminal region. A representative allele is c.1040T>C (p.Leu347Pro), detected in an affected sib-pair and predicted to destabilize kinase activity and mitochondrial targeting.

Functional studies demonstrate that PINK1 loss impairs mitochondrial integrity and antioxidant defenses. Patient fibroblasts homozygous for p.Gly309Asp exhibit increased lipid peroxidation, reduced complex I activity and elevated glutathione-S-transferase expression (PMID:17141510). In human neuronal cell lines, wild-type PINK1—but not disease-associated mutants—suppresses staurosporine-induced cytochrome c release and caspase activation, underscoring a neuroprotective kinase function (PMID:16079129).

In vivo, Drosophila Pink1 loss causes dopaminergic neuron degeneration and muscular defects that are rescued by human PINK1 expression, confirming conserved mitochondrial regulation in a PARKIN-linked pathway (PMID:16818890).

Collectively, strong genetic segregation and robust functional concordance across cellular and animal models support a model of PINK1 haploinsufficiency and loss-of-kinase-activity as the mechanism underlying PARK6. PINK1 genetic testing is clinically warranted in early-onset parkinsonism, facilitating diagnosis, family counseling, and patient stratification for emerging mitochondrial-targeted therapies.

References

• Annals of neurology | 2004 | Novel PINK1 mutations in early-onset parkinsonism. PMID:15349870
• Neurobiology of disease | 2007 | Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. PMID:17141510
• 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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