Fifteen years of genetic research in Parkinson’s disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD. Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established, albeit relatively rare types of PD. They collectively account for about 30% of the familial and 3%–5% of the sporadic cases. In this article, we will summarize the current knowledge and understanding of the molecular genetics of PD. In brief, we will review familial forms of PD, basic genetic principles of inheritance (and their exceptions in PD), followed by current methods for the identification of PD genes and risk factors, and implications for genetic testing.

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Genetics of Parkinson’s Disease

The degeneration of forebrain dopamine systems in Parkinson's disease has been an effective target for pharmaceutical research over the past four decades. However, although dopamine replacement may alleviate the symptoms of the disease, it does not halt the underlying neuronal degeneration. The past decade has seen major advances in identifying discrete genetic and molecular causes of parkinsonism and mapping the events involved in nigral cell death. This new understanding of the pathogenesis of the disease now offers novel prospects for therapy based on targeted neuroprotection of vulnerable neurons and effective strategies for their replacement.

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Prospects for new restorative and neuroprotective treatments in Parkinson's disease

Autosomal recessive juvenile parkinsonism (AR-JP, PARK2; OMIM 602544), one of the monogenic forms of Parkinson's disease (PD), was initially described in Japan. It is characterized by early onset (before age 40), marked response to levodopa treatment and levodopa-induced dyskinesias, The gene responsible for AR-JP was recently identified and designated parkin, We have analysed the 12 coding exons of the parkin gene in 35 mostly European families with early onset autosomal recessive parkinsonism. In one family, a homozygous deletion of exon 4 could be demonstrated. By direct sequencing of the exons in the index patients of the remaining 34 families, eight previously undescribed point. mutations (homozygous or heterozygous) were detected in eight families that included 20 patients, The mutations segregated with the disease in the families and were not detected on 110-166 control chromosomes. Four mutations caused truncation of the parkin protein. Three were frameshifts (202-203delAG, 255delA and 321-322insGT) and one a nonsense mutation (Trp453Stop). The other four were missense mutations (Lys161Asn, Arg256Cys, Arg275Trp and Thr415Asn) that probably affect amino acids that are important for the function of the parkin protein, since they result in the same phenotype as truncating mutations or homozygous exon deletions. Mean age at onset was 38 +/- 12 years, but onset up to age 58 was observed. Mutations in the parkin gene are therefore not invariably associated with early onset parkinsonism. In many patients, the phenotype is indistinguishable from that of idiopathic PD. This study has shown that a wide variety of different mutations in the parkin gene are a common cause of autosomal recessive parkinsonism in Europe and that different types of point mutations seem to be more frequently responsible for the disease phenotype than are deletions.

/pdf/a-wide-variety-of-mutations-in-the-parkin-gene-are-3m980xfqpl.pdf

A Wide Variety of Mutations in the Parkin Gene Are Responsible for Autosomal Recessive Parkinsonism in Europe

The presynaptic protein α-synuclein is a prime suspect for contributing to Lewy pathology and clinical aspects of diseases, including Parkinson's disease, dementia with Lewy bodies, and a Lewy body variant of Alzheimer's disease. α-Synuclein accumulates in Lewy bodies and Lewy neurites, and two missense mutations (A53T and A30P) in the α-synuclein gene are genetically linked to rare familial forms of Parkinson's disease. Under control of mouse Thy1 regulatory sequences, expression of A53T mutant human α-synuclein in the nervous system of transgenic mice generated animals with neuronal α-synucleinopathy, features strikingly similar to those observed in human brains with Lewy pathology, neuronal degeneration, and motor defects, despite a lack of transgene expression in dopaminergic neurons of the substantia nigra pars compacta. Neurons in brainstem and motor neurons appeared particularly vulnerable. Motor neuron pathology included axonal damage and denervation of neuromuscular junctions in several muscles examined, suggesting that α-synuclein interfered with a universal mechanism of synapse maintenance. Thy1 transgene expression of wild-type human α-synuclein resulted in similar pathological changes, thus supporting a central role for mutant and wild-type α-synuclein in familial and idiotypic forms of diseases with neuronal α-synucleinopathy and Lewy pathology. These mouse models provide a means to address fundamental aspects of α-synucleinopathy and test therapeutic strategies.

https://www.jneurosci.org/content/jneuro/20/16/6021.full.pdf

Neuropathology in Mice Expressing Human α-Synuclein

http://www.jbc.org/content/275/1/390.full.pdf

Constitutive Phosphorylation of the Parkinson's Disease Associated α-Synuclein *

A mutation in exon 4 of the alpha-synuclein (NACP) gene has been reported to explain the chromosome 4 linkage to autosomal dominant Parkinson's disease. We developed primers and methods for exonic sequencing of this gene and sequenced the entire coding region of the gene in 6 families with autosomal dominant disease and in 2 cases of lytico and bodig from Guam. In addition, we have sequenced exon 4 of this gene in 5 cases of familial disease and have screened for the specific mutation (A53T) in a 40 cases of idiopathic Parkinson's disease, 3 cases of multisystem atrophy, and 15 cases of Lewy body dementia. We have found no genetic variation in the gene. We discuss these findings with respect to both the epidemiology of Parkinson's disease and the possibility that NACP is not the chromosome 4 locus for disease.

F Wavrant-De Vrieze

Papers

Low frequency of alpha-synuclein mutations in familial Parkinson's disease