An international study led by the Mayo Clinic has found a mechanism that may help explain Parkinson’s and other neurological disorders.
Studying just eight families worldwide, the international team of researchers have discovered a genetic defect that results in profound depression and Parkinsonism in a disorder known as Perry syndrome.
Although this syndrome is exceedingly rare, the mechanism implicated in it may help explain the origins of a variety of neurodegenerative disorders, such as Parkinson’s and amyotrophic lateral sclerosis diseases, and even common depression and sleep disorders that are also hallmarks of the disorder, the researchers say.
In the study, to be published in the February issue of Nature Genetics (online January 11), the researchers report that people with Perry syndrome have mutations in a subunit of the dynactin complex (DCTN1; p150glued), which is essential to the movement of molecular “cargo” inside brain cells, or neurons.
In this case, the mutations meant that the cargo was being driven on a “train” that essentially had faulty brakes. And because Perry syndrome resembles many other neurodegenerative diseases, the findings suggest breakdowns along the cell’s interior transportation grid may be a common mechanism underlying neurodegeneration.
“Understanding why distinct neurons are selectively vulnerable to neurodegeneration in different brain disorders is one of the greatest puzzles in neuroscience,” says the study’s lead investigator, Matthew J. Farrer, Ph.D., a professor of neuroscience at Mayo Clinic.
“These findings suggest that trafficking of specific cargoes inside brain cells may be a general problem in a variety of neurodegenerative diseases, depression, and other disorders.”
“It points us to a unified theory of what is going wrong in many of them,” says the study’s senior author, Zbigniew K. Wszolek, M.D., professor of neurology at Mayo Clinic.
Molecules, vesicles and organelles within a cell are constantly carried via a network of crisscrossing microtubules that act like the tracks of an elaborate railroad system. Because, for the most part, neurons do not regenerate or divide as do other cells in the body, trafficking cargo efficiently over the lifetime of a neuron is fundamentally important, says Dr. Farrer.
Disruptions in this railroad system have been seen in many neurodegenerative diseases, but these problems have been generally regarded as byproducts of the disorder rather than the cause, the researchers say. These new findings may change that view, they say.
For example, in amyotrophic lateral sclerosis (ALS), a motor neuron disease also known as Lou Gehrig’s disease, the molecular motors (for example, dynein, dynactin and kinesin) that drive transport from distant nerve terminals to the cell body may become defective.
In some forms of Parkinson’s disease, growing evidence indicates that the cargoes being trafficked are also misdirected by faulty signaling, due to pathogenic mutations in the leucine-rich repeat kinase 2(LRRK2) gene, Dr. Farrer says.
The findings may also shed light on other neurodegenerative disorders, the researchers say. In Alzheimer’s disease, frontotemporal dementia and progressive supranuclear palsy, for instance, the “spikes,” comprised of microtubule associated protein tau (MAPT), that normally stabilize and secure these rails tend to fall apart.
This discovery would not have been possible without a consortium of international researchers including co-authors from Canada, France, Japan, Turkey, and the United Kingdom, says Dr. Wszolek, who established the collaborative network of scientists.
Source: Mayo Clinic