The overall goal of the lab is to understand the molecular mechanisms of neurodegeneraton using tissue culture and mouse modeling, based on insights from human genetics.
Neurodegeneration in the peripheral nervous system has classically been divided into two forms - (1) neuropathy, characterized by length dependent axonal degeneration without cell body loss, and (2) neuronopathy, characterized by non-length dependent motor or sensory neuron degeneration. To understand mechanisms of peripheral neuropathy we are focusing on inherited forms of the disease, known as Charcot-Marie-Tooth disease. The molecular pathways defined by genes mutated in hereditary axonal neuropathy are critical for the maintenance of long peripheral axons, and are potential candidates for therapeutic manipulation. To investigate mechanisms of neuronopathy we are exploring the role of mutations in the TDP-43 protein in inherited motor neuron disease (aka amyotrophic lateral sclerosis or Lou Gehrig's disease).
Role of TDP-43 mutations in motor neuron disease and frontotemporal lobar degeneration
Motor neuron disease/amyotrophic lateral sclerosis (ALS) is the prototypic neurodegenerative disease involving the neuromuscular system. Patients with ALS develop progressive weakness, muscle wasting and stiffness due to degeneration of both upper and lower motor neurons in the brain and spinal cord. Though most cases occur without a family history, approximately 10% of cases are inherited. The most well characterized gene responsible for familial ALS is SOD1, but this represents only 20% of families, leaving the genetic cause of the majority of familial ALS cases unknown. Aggregates of ubiquitinated TDP-43 are found in both ALS and frontotemporal lobar dementia with ubiquitinated inclusions (FTLD-U), defining a unifying pathology for these two clinically overlapping neurodegenerative diseases. The recent identification of mutations in TDP-43 and FUS/TLS segregating with dominantly inherited motor neuron disease implicate RNA binding proteins as being directly involved in the pathogenesis of ALS/FTLD-U. We are developing in vitro and mouse models to investigate how mutations in TDP-43 and other RNA binding proteins lead to motor neuron disease.
Role of mitochondrial dynamics (fusion, fission and movement of mitochondria) in neurodegeneration
Mitochondria are highly dynamic structures, constantly moving, fusing together and dividing. Though recognized since the early 20th century, the importance of these processes to maintain proper mitochondrial function has only recently been explored. Mutations in two outer mitochondrial membrane proteins (MFN2 and GDAP1) have been identified in patients with inherited peripheral neuropathy, and we are exploring the mechanism(s) by which these lead to selective distal axonal degeneration in peripheral neurons. Our initial studies using live imaging of mitochondrial dynamics in cultured neurons suggests that the disruption of mitochondrial transport and distribution may be a key player in the selective degeneration of long peripheral axons from MFN2 mutations. Ongoing studies involve understanding how altered mitochondrial transport leads to axonal degeneration, and ultimately how to develop therapeutic agents to either ameliorate the mitochondrial transport defect or diminish the axonal degeneration that develops as a consequence of mitochondrial dysfunction.
Improving genetic diagnosis in patients with inherited neuromuscular diseases:
Making an exact genetic diagnosis in patients with inherited neuromuscular diseases is critical for genetic counseling, inclusion into clinical trials, and in the future will be used to decide on appropriate therapeutic agents. Despite the remarkable advances in human genetics many patients with inherited neuromuscular disorders remain undiagnosed because of cost or lack of available testing. We are collecting blood and tissue samples from all patients with inherited neuromuscular diseases seen at the at Cedars-Sinai Medical Center Neuromuscular Disorders clinic with the goal of using novel technologies in molecular diagnostics to eventually make an exact genetic diagnosis in all of our patients (list a hyperlink to clinical site - Robert Baloh, MD, PhD to provide).
We receive funding from the following organizations: