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The overall goal of the Baloh Laboratory is to understand the molecular mechanisms of neurodegeneration using human genetics as a roadmap to define how to develop novel therapeutics. The Baloh Lab uses stem cell-based "disease in a dish" models and transgenic animal models to investigate treatments for diseases that currently are incurable, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and inherited neuropathy (Charcot-Marie-Tooth disease).
Investigations Into ALS and Frontotemporal Dementia
Amyotrophic lateral sclerosis (a.k.a., motor neuron disease or Lou Gehrig’s disease or 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. A subset of ALS patients also develops degeneration outside of the motor system leading to frontotemporal dementia (FTD), with cognitive and behavioral deficits in addition to motor weakness. Though most cases occur without a family history, approximately 10 percent of ALS cases are inherited. These cases provide unique insight because they tell us which cellular components can go wrong to cause the disease.
The Role of C9ORF72 Hexanucleotide Expansion in ALS and FTD
Expansions of a repeated sequence (GGGGCC) in the noncoding region of the C9ORF72 gene are the most common cause of inherited and sporadic ALS and FTD. The Baloh Lab is investigating how this repeat expansion alters the expression of the C9ORF72 gene and leads to the accumulation of potentially toxic RNA and protein products that may promote neurodegeneration. The image below shows motor neurons from a control patient (left) and an ALS patient with the C9ORF72 mutation (right). The patient’s neurons have a large number of nuclear foci containing the GGGGCC repeat, a pathologic finding characteristic of this form of ALS.
TDP-43 — An ALS Disease Gene That Forms the Characteristic Protein Aggregates in ALS/FTLD
Aggregates of ubiquitinated TDP-43 are found in both ALS and FTLD with ubiquitinated inclusions, and define the characteristic pathology for these two clinically overlapping neurodegenerative diseases. Furthermore, mutations in TDP-43 can cause ALS, directly implicating the function of this RNA-binding protein in the pathogenesis of ALS. The Baloh Laboratory developed the first transgenic mouse model of TDP-43 related neurodegeneration, and using this and other models, we are investigating how mutations in TDP-43 and other RNA binding proteins lead to neurodegeneration.
Investigations Into Peripheral Nerve Degeneration
To understand mechanisms of peripheral nerve degeneration we are focusing on inherited neuropathy (a.k.a., Charcot-Marie-Tooth disease or CMT). Degeneration of peripheral nerves leads to weakness, muscle atrophy and sensory loss. In CMT this process is particularly pronounced in the longest nerves, often affecting the feet earliest, later progressing to the lower legs and hands, leading to significant disability. The Baloh Lab is using induced pluripotent stem cells (iPSCs) derived from patients with various forms of CMT to understand how both axons and Schwann cells become dysfunctional in peripheral nerve disease and to test ways to protect peripheral nerves from degenerating.
Human iPSC Modeling and Therapeutics for Degenerative Peripheral Nerve Disease
CMT1A is the most common form of inherited nerve disease, and is caused by the duplication of a gene called PMP22. PMP22 is a key protein in the Schwann cells that ensheath and support peripheral axons, and altered dosage of this protein compromises the ability of Schwann cells to support axons, eventually leading to axon degeneration. To study this disease we have taken skin cells from patients with CMT1A and converted them into iPSCs and Schwann cell precursors. The Baloh Lab is investigating the abnormalities in these patients’ cells in culture and animal models, to develop therapies for CMT1A and other diseases caused by myelin damage with secondary axon loss. The image below shows green fluorescent protein (GFP)-labeled human Schwann cell precursors transplanted into rat peripheral nerve.
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 in maintaining 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 the Baloh Lab is exploring the mechanism(s) by which these lead to selective distal axonal degeneration in peripheral neurons. Our 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.
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