Genetics and genomics of Parkinson's disease

被引:139
作者
Lin, Michelle K. [1 ]
Farrer, Matthew J. [1 ]
机构
[1] Univ British Columbia, Dept Med Genet, Djavad Mowafaghian Ctr Brain Hlth, Ctr Appl Neurogenet, Vancouver, BC V6T 1Z3, Canada
关键词
AUTOSOMAL-DOMINANT PARKINSONISM; ALPHA-SYNUCLEIN; EARLY-ONSET; MITOCHONDRIAL DYSFUNCTION; DEPENDENT ENDOCYTOSIS; WIDE ASSOCIATION; COMMON VARIANTS; VPS35; MUTATIONS; KINASE-ACTIVITY; LRRK2;
D O I
10.1186/gm566
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Parkinson's disease (PD) is a progressively debilitating neurodegenerative syndrome. Although best described as a movement disorder, the condition has prominent autonomic, cognitive, psychiatric, sensory and sleep components. Striatal dopaminergic innervation and nigral neurons are progressively lost, with associated Lewy pathology readily apparent on autopsy. Nevertheless, knowledge of the molecular events leading to this pathophysiology is limited. Current therapies offer symptomatic benefit but they fail to slow progression and patients continue to deteriorate. Recent discoveries in sporadic, Mendelian and more complex forms of parkinsonism provide novel insight into disease etiology; 28 genes, including those encoding alpha-synuclein (SNCA), leucine-rich repeat kinase 2 (LRRK2) and microtubule-associated protein tau (MAPT), have been linked and/or associated with PD. A consensus regarding the affected biological pathways and molecular processes has also started to emerge. In early-onset and more a typical PD, deficits in mitophagy pathways and lysosomal function appear to be prominent. By contrast, in more typical late-onset PD, chronic, albeit subtle, dysfunction in synaptic transmission, early endosomal trafficking and receptor recycling, as well as chaperone-mediated autophagy, provide a unifying synthesis of the molecular pathways involved. Disease-modification (neuroprotection) is no longer such an elusive goal given the unparalleled opportunity for diagnosis, translational neuroscience and therapeutic development provided by genetic discovery.
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页数:16
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