Abstract
Parkinson disease is a complex disease that has multiple genetic and environmental factors. To achieve the early diagnosis and to be able to modify the disease progression, efforts are being made to identify individuals at risk. About 20 year ago, an evidence of major prevalence of Parkinsonism in patients with Gaucher Disease reported by studies worldwide led to the putative involvement of the GBA gene. Nowadays, the link from a rare disease with a common disease is well known and it is confirmed that mutations in the GBA gene are the most important genetic risk factor. Apart from rare mutations, genetic association studied appointed common variants in genes well associated with familial cases as LRRK2 and SNCA may also contribute to the increased risk for sporadic cases. Other common variants in the MAPT gene were also reported. At least, genetic studies have been observed an excessive burden of relevant variants in genes with lysosomal function. Thus, a synergistic action of variants in genes that codifies proteins involved with the lysosome may be a mean of modulating the risk. In this chapter, we review the most robust genetic risk factor and the relevance of lysosomal function for Parkinson disease.
Highlights
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease in humans and it is characterized by motor symptoms as muscular rigidity, resting tremor, bradykinesia, and postural instability and by nonmotor symptoms
The most robust and consistently replicated results are appointed to variants in the genes LRRK2, MAPT, SNCA and GBA, the last being the major genetic risk factor highlighting the importance of lysosomal pathway in the pathogenesis of PD [1–8]
The GBA gene was initially described in association with a rare lysosomal storage disease (LSD) called Gaucher disease (GD)
Summary
Parkinson’s disease (PD) is the second most common progressive neurodegenerative disease in humans and it is characterized by motor symptoms as muscular rigidity, resting tremor, bradykinesia, and postural instability and by nonmotor symptoms (hyposmia, constipation, depression, dementia, and postural hypotension, among others). These symptoms result primarily from the progressive loss of the dopaminergic neurons from the pars compacta of the mesencephalic substantia nigra and subsequent depletion of the dopamine neurotransmitter in the striatum, a central component of the basal ganglia that is responsible for the instigation and coordination of movements (Figure 1). The definitive diagnosis of PD is difficult being only confirmed with the presence of Lewy bodies, proteinaceous intracytoplasmic inclusion, in the reminiscent neurons of substantia nigra pars compacta and other regions in the brain postmortem analysis [1]
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