Author Affiliations: Institute of Neurogenetics, University of Lübeck, Germany (Dr Klein); and Department of Neurology, Massachusetts General Hospital, Institute for Neurodegenerative Disease, Harvard Medical School, Boston, Massachusetts (Dr Krainc).
The accumulation and aggregation of mutant proteins that are commonly observed in different neurodegenerative disorders is suggestive of a shared pathogenic mechanism. Recent data indicate that the elimination of the accumulation of mutant proteins can halt the symptomatic progression of neurodegeneration and can also lead to the regression of disease. This has been best demonstrated through conditional mouse models, in which the elimination of the expression of disease-linked proteins such as α-synuclein (SNCA) and mutant huntingtin resulted in a reversal of the pathological phenotype. The evidence is most compelling in Parkinson disease (PD) because clinical and genetic studies point to a clear dosage relationship between SNCA and disease. For example, a duplication of 1 of the 2 wild-type SNCA alleles can lead to parkinsonism similar to idiopathic PD in about one-half of the mutation carriers. However, 1 additional copy (triplication of 1 of the 2 wild-type alleles) confers full penetrance with clinical features that can encompass PD and dementia with Lewy bodies (DLB). Therefore, alterations in expression levels of SNCA are sufficient to cause a wide spectrum of disease.1 These findings hold promise for potential causative treatment approaches: if SNCA can somehow be cleared, the disease could possibly be reversed or even prevented. Clearance of aggregation-prone proteins is largely achieved through the autophagy-lysosomal system. However, one of the main challenges is to identify the specific mechanisms and targets involved in the clearance of these proteins in order to develop specific therapeutics. Recent studies of rare lysosomal storage disorders that commonly exhibit neurodegeneration and are caused by mutations in genes involved in lysosomal function have offered intriguing and novel insights into the pathogenesis of neurodegeneration.
Klein C, Krainc D. Glucocerebrosidase MutationsTipping Point Toward Parkinson Disease and Dementia?. JAMA Neurol. 2013;70(6):686-688. doi:10.1001/jamaneurol.2013.87