An exciting new discovery on a genetic mutation that appears to be associated with Parkinson’s disease once again brings hope to some PD patients. Parkinson’s disease is gradually progressive neurodegenerative disorder manifested due to the loss of dopamine producing nerve cells, which are predominantly situated in a crescent shaped region of of the brain called as nigro-striatum. The main causes and pathophysiology of Parkinson’s disease is still not well understood. However various familial and genetic factors have been found to play a crucial role in the development of disease.
The genes undergo mutations and somehow alter the dopamine related biochemical processes in the brain. One such mutation in the gene known as VPS35, was identified in a large Swiss family with a history of Parkinson’s disease. While this may not be applicable for every case of Parkinson’s disease, it does open up possibilities about further understanding the genetic mechanisms related to certain cases where there is a strong family history of PD.
The study which appeared in the American Journal of Human Genetics (July 2011 issue) involved a global collaboration with researchers from the United States, United Kingdom, Canada, Europe and Asia. The research was led by Mayo Clinic neuroscientists and funded by several organizations, including in part by the Michael J. Fox Foundation.
The biochemical processes in Parkinson’s disease, particularly at the cellular level, is complex and not completely understood. VPS35 is the vacuolar protein sorting 35 homolog gene, situated at the PARK 17 locus, and encodes a key component of the retromer complex. The study has indicated that the VPS35 gene mutation disrupts the nerve cells’ (neurons) ability to recycle proteins facilitated by special protein complexes known as retromers. A faulty retromer therefore cannot play the integral role it usually does in the normal protein recycling process. Mutations in VPS35 gene has been recently discovered as a new cause of late onset, autosomal dominant Parkinson’s disease. A single VPS35 missense mutation has been found in a number of PD patients and families worldwide, and are considered to be the second most common form of late-onset familial Parkinson’s disease after LRRK2 mutations. However, the pathophysiological mechanism by which VPS35 mutations precipitate dominant PD is not yet known. Other genes responsible for Parkinson’s disease have been listed in the section of ‘family history and genetics’ of the article who gets parkinson’s disease.
An exome is defined as the protein coding sequence of the human genome. A new genetic sequencing technique was used by the scientists to find the VPS35 mutation in first cousins of the large Swiss family with a strong history of Parkinson’s disease. By sequencing just the exome, the portion of the genome responsible for manufacturing proteins, the genetic mutation was discovered without the more costly and time consuming process of analyzing the entire genome. It is a fundamental tool for genetics and functional genomics laboratories. It generates a faster and a relatively manageable database to analysed and studied by the scientists in comparison to the whole genome sequencing. Exomes constitute less than 2% of the human genome, but since it contains approximately 85% of known disease related variants, its sequencing allow the scientists to identify genetic variations that causes changes in specific protein sequences in a focussed way.
The exome sequencing has uncovered the layers of VPS35 induced PD pathophysiology to some extent. It hypothesizes the process of mitochondrial dysfunction caused as a result of autosomal dominant missense mutation in VPS35 gene. Studies have shown mitochondrial fragmentation and cell death in the in-vitro cultured rat’s nigro-striatal neurons having VPS35 mutation. However, the mechanism of advent of nigrostriatal dopaminergic neuronal degeneration is still a mystery.
This latest discovery adds to the five other genetic mutations already found to be associated with Parkinson’s disease. However, the VPS35 mutation discovery is not applicable to every case of PD and is more likely associated with late-onset familial Parkinson’s disease. Furthermore the mutation may not only be significant for Parkinson’s disease, as its reduced gene expression was also seen with other neurodegenerative diseases like Alzheimer’s disease.
Clinical Significance of the VPS35 Discovery
The clinical significance of this discovery cannot as yet be fully appreciated but may go a long way in contributing to the development of specific drugs that can target the subsequent biochemical disruption associated with the VPS35 mutation and the development of autosomal dominant familial late onset Parkinson’s disease. The gene VPS35 possess a broad neuronal distribution in the rodent brain, including the nigro-striatal dopaminergic pathway. Humans are found to have a similar distribution of this gene, both in the control subjects and the PD patients under study.
VPS35 gene is known to encode for a protein complex known as retromer, whose primary function is to recycle other proteins within the cells. Somehow, an autosomal dominant missense mutation caused in this gene, impairs the ability of the retromer complex to recycle other proteins as normally needed. It eventually leads to an erroneous protein build up in the cell, which are characteristically seen in the post-mortem brain biopsy results of the patients, who suffered through Parkinson’s disease. To sum up, the errant protein build up is a result of failure of retromer complex and mitochondrial dysfunction, but the mechanism as to how this protein build up initiates the neurological degeneration in the nigro-striatal dopaminergic pathway is still unclear.
Thus, there is still a significant amount of research that has still has to be done surrounding this discovery and as one of the co-authors of the study, Own Ross (Ph.D.) stated, “… it appears to be a rare cause of Parkinson’s disease …”. Nevertheless, every discovery in the study of Parkinson’s disease holds new hope for all PD patients and contributes to a greater understanding of the disease as a whole.
As another co-author of the study, Zbigniew Wszolek (M.D.) , so accurately pointed out, “This finding provides an exciting new direction for Parkinson’ s disease research. Every new gene we discover for Parkinson’s disease opens up new ways to understand this complex disease, as well as potential ways of clinically managing it.”