Impact of recent genetic findings in Parkinson's disease.
OBJECTIVE
Parkinson's disease is the second most common age-related neurodegenerative disorder and is characterized clinically by classical parkinsonism and pathologically by selective loss of dopaminergic neurons in the substantia nigra and Lewy bodies. Although for most classical parkinsonism the etiology is unknown, a clear genetic component has been determined in a minority. Mutations in five causative genes combined [alpha-Synuclein (SNCA), Parkin, PTEN-induced kinase 1 (PINK1), DJ-1, Leucine-rich repeat kinase 2 (LRRK2)] account for 2-3% of all cases with classical parkinsonism, often clinically indistinguishable from idiopathic Parkinson's disease.


RESULTS
The functional role of PINK1 and LRRK2 as kinases has been clearly established. Further, mutations in the ATP13A2 gene have been linked to Kufor-Rakeb syndrome (PARK9), a form of atypical parkinsonism. ATP13A2 encodes a lysosomal ATPase and shows elevated expression levels in the brains of sporadic patients, suggesting a potential role in the more common idiopathic Parkinson's disease. Finally, first promising pilot studies have been performed to identify differentially expressed genes and proteins as biomarkers for parkinsonism.


CONCLUSIONS
The identification of single genes and their functional characterization has enhanced our understanding of the pathogenesis of parkinsonism, has led to improvement of diagnostic tools for genetic parkinsonism, and allows for the purposeful consideration of novel therapeutic targets.
Klein
Christine
C
Departments of Neurology and Human Genetics, Lübeck University, Lübeck, Germany. christine.klein@neuro.uni-luebeck.de
Lohmann-Hedrich
Katja
K
D003937:Diagnosis, Differential; D020022:Genetic Predisposition to Disease; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000145:classification / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism; D000099202:PTEN-Induced Putative Kinase
D047908:Intracellular Signaling Peptides and Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D051844:alpha-Synuclein; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C495280:LRRK2 protein, human; C105131:PARK7 protein, human