Parkin and PINK1 parkinsonism may represent nigral mitochondrial cytopathies distinct from Lewy body Parkinson's disease.

Abstract

Recent authors have concluded that Parkinson's disease (PD) is too heterogeneous to still be considered a single discrete disorder. They advise broadening the concept of PD to include genetic parkinsonisms, and discard Lewy pathology as the confirmatory biomarker. However, PD seen in the clinic is more homogeneous than often recognized if viewed from a long-term perspective. With appropriate diagnostic criteria, it is consistently associated with Lewy neuropathology, which should remain the gold standard for PD diagnostic confirmation. PD seen in the clinic has an inexorable course with eventual development of not only levodopa-refractory motor symptoms, but often cognitive dysfunction and prominent dysautonomia. This contrasts with homozygous parkin, PINK1 or DJ1 parkinsonism, characterized by young-onset (usually <40 years), and a comparatively benign course of predominantly levodopa-responsive symptoms without dementia or prominent dysautonomia. Parkin neuropathology is non-Lewy, with neurodegeneration predominantly confined to substantia nigra (and locus ceruleus), consistent with the limited clinical phenotype. Given the restricted and persistently levodopa-responsive phenotype, these familial cases might be considered "nigropathies". Based on emerging laboratory evidence linking parkin and PINK1 (and perhaps DJ1) to mitochondrial dysfunction, these nigropathies may represent nigral mitochondrial cytopathies. The dopaminergic substantia nigra is uniquely vulnerable to mitochondrial challenges, which might at least be partially attributable to large energy demands consequent to thin, unmyelinated axons with enormous terminal fields. Although sporadic PD is also associated with mitochondrial dysfunction, Lewy neurodegeneration represents a more pervasive disorder with perhaps a second, or different primary mechanism.

• Authors: J Eric Ahlskog
• Journal: Parkinsonism & related disorders (Parkinsonism Relat Disord) Vol. 15 Issue 10 Pg. 721-7 (Dec 2009) ISSN: 1873-5126 [Electronic] England
• PMID: 19815446 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Intracellular Signaling Peptides and Proteins
• Oncogene Proteins
• alpha-Synuclein
• Ubiquitin-Protein Ligases
• parkin protein
• Protein Kinases
• PTEN-induced putative kinase
• PARK7 protein, human
• Protein Deglycase DJ-1

Topics

• Disease Progression
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• Male
• Middle Aged
• Mitochondria (pathology)
• Oncogene Proteins (metabolism)
• Parkinson Disease (diagnosis, genetics, metabolism)
• Parkinsonian Disorders (diagnosis)
• Protein Deglycase DJ-1
• Protein Kinases (genetics, metabolism)
• Substantia Nigra (pathology)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• alpha-Synuclein (metabolism)