It has been a good 10 years since the first disease-causing mutation in the α-synuclein gene (SNCA) was described in a family with autosomal-dominant Parkinson disease. However, in spite of a decade of intense research, only three pathogenic SNCA mutations have been identified (see SNCA on PDGene). Instead, investigators have found that carriership of an extra wild-type SNCA copy may be a more common genetic cause for this disease. Duplications, i.e., one extra SNCA copy, result in a phenotype indistinguishable from sporadic Parkinson disease, whereas triplications, i.e., two extra SNCA copies, cause a more severe clinical picture, including earlier disease onset and variable degrees of cognitive impairment. This is in stark contrast to Alzheimer disease, where more than 200 different causative mutations in the APP and presenilin genes have been described, but APP duplication remains extremely rare (see   Read more

It has been a good 10 years since the first disease-causing mutation in the α-synuclein gene (SNCA) was described in a family with autosomal-dominant Parkinson disease. However, in spite of a decade of intense research, only three pathogenic SNCA mutations have been identified (see SNCA on PDGene). Instead, investigators have found that carriership of an extra wild-type SNCA copy may be a more common genetic cause for this disease. Duplications, i.e., one extra SNCA copy, result in a phenotype indistinguishable from sporadic Parkinson disease, whereas triplications, i.e., two extra SNCA copies, cause a more severe clinical picture, including earlier disease onset and variable degrees of cognitive impairment. This is in stark contrast to Alzheimer disease, where more than 200 different causative mutations in the APP and presenilin genes have been described, but APP duplication remains extremely rare (see mutation database.

In the current study, Ibanez and colleagues set out to undertake a comprehensive screening for SNCA multiplications in a collection of more than 250 families with a seemingly dominant inheritance pattern of Parkinson disease. Four duplication and one triplication families were identified, and affected individuals described the expected clinical characteristics. In addition, the authors were able to elegantly define the duplicated region boundaries and concluded that the multiplied sequences span different distances in different families, ranging from SNCA alone to including more than 30 nearby genes. Interestingly, unlike the SNCA copy numbers, the number of other multiplied genes was not found to affect the clinical picture.

These findings strongly indicate that SNCA is the sole disease-causing gene in patients with SNCA duplications. They reinforce the pathological relevance of augmented α-synuclein levels in Lewy body formation and neuronal dysfunction in Parkinson disease.

View all comments by Martin Ingelsson

The discovery that multiplications of the alpha-synuclein gene cause autosomal-dominant Parkinson disease was one of the major findings in recent years that helped to understand the molecular pathogenesis of this common movement disorder. It proved that an increase in gene dosage and consequently an increase in protein expression is harmful to neurons. Multiplication of the alpha-synuclein gene causes all the pathologic and clinical changes also found in common sporadic synucleinopathies from idiopathic Parkinson disease to Lewy body dementia, and also shares features with another important synucleinopathy, namely multiple system atrophy.

This study by Ibanez et al. is the most comprehensive study of genomic rearrangements of the alpha-synuclein gene in a large series of families with typical or atypical autosomal-dominantly inherited Parkinsonism. The major finding is that 1.5 percent of typical autosomal-dominant PD is caused by alpha-synuclein duplications, while 1 out of 22 families (4.5 percent) of families with atypical Parkinsonism carried a triplication of the gene....  Read more

The discovery that multiplications of the alpha-synuclein gene cause autosomal-dominant Parkinson disease was one of the major findings in recent years that helped to understand the molecular pathogenesis of this common movement disorder. It proved that an increase in gene dosage and consequently an increase in protein expression is harmful to neurons. Multiplication of the alpha-synuclein gene causes all the pathologic and clinical changes also found in common sporadic synucleinopathies from idiopathic Parkinson disease to Lewy body dementia, and also shares features with another important synucleinopathy, namely multiple system atrophy.

This study by Ibanez et al. is the most comprehensive study of genomic rearrangements of the alpha-synuclein gene in a large series of families with typical or atypical autosomal-dominantly inherited Parkinsonism. The major finding is that 1.5 percent of typical autosomal-dominant PD is caused by alpha-synuclein duplications, while 1 out of 22 families (4.5 percent) of families with atypical Parkinsonism carried a triplication of the gene. This makes gene rearrangements clearly a more frequent cause of inherited Parkinsonism than point mutations. It clearly confirms and supports earlier reports that the gene dose and hence the level of protein expression is the crucial determinant of the phenotype.

This is not only of major importance for rare families with clearly defined genetic disease but also for the common sporadic disorders. In these, research efforts should focus on mechanisms of alpha-synuclein regulation, which are likely to be a major cause of the sporadic disorder.

View all comments by Thomas Gasser