Welcome to the Weihl Lab
Our goal is to understand the molecular mechanisms of protein inclusion formation and clearance in myodegenerative (skeletal muscle) and neurodegenerative diseases. We believe that dysfunction in protein degradation pathways (e.g. the ubiquitin proteasome system, endoplasmic reticulum associated degradation and autophagy) disrupt cellular protein homeostasis resulting in degenerative phenotypes and normal aging. We employ complementary experimental techniques such as biochemistry, cell culture, animal models, and patient tissue to achieve these goals.
My lab is particularly interested in the pathogenesis of inclusion body myopathy, paget’s disease of the bone and frontotemporal dementia or IBMPFD, a multisystem degenerative disorder due to missense mutations in p97/VCP/cdc48. IBMPFD muscle and brain tissue contains ubiquitinated protein inclusions associated with cellular degeneration and vacuolation.
1) How IBMPFD mutations in VCP lead to these pathologic features and 2) what is the normal function of VCP in protein degradation pathways are the fundamental questions being addressed by our research.
Inclusion body myopathy, paget’s disease of the bone and frontotemporal dementia or IBMPFD,is a multisystem degenerative disorder due to missense mutations in the multifunctional AAA+ ATPase, p97/VCP/cdc48. IBMPFD is autosomal dominantly inherited disorder and has three variably penetrant phenotypes: inclusion body myopathy (IBM), paget’s disease of the bone (PDB), and frontotemporal dementia (FTD). Other phenotypes have been described including cardiomyopathy, cataracts and neuropathy.
Clinical Phenotypes in IBMPFD:
IBM is characterized by progressive debilitating weakness affecting both the upper and lower extremities. Patients can present with syndromes mimicking limb-girdle muscular dystrophy, fascioscapulohumeral dystrophy or a distal myopathy.
PDB is a progressive bone disorder due to excessive breakdown and formation of bone tissue resulting in characteristic lytic lesions on autoradiography. This causes bone to weaken, resulting in bone pain, arthritis, deformities, and fractures.
FTD is the second most common cause of senile dementia. Unlike Alzheimer’s dementia, FTD patients have preserved working memory early in the disease course and instead have personality changes such as disinhibition along with difficulties in speech production, attention, reasoning and language.
Pathologic features of IBMPFD:
Skeletal muscle contains several characteristic features consistent with IBM including (A) rimmed vacuoles and (B) intranuclear and sarcoplasmic ubiquitinated protein inclusions. In additon, we have identified (C) intranuclear and sarcoplasmic VCP and (D) sarcoplasmic TDP-43 positive inclusions.
Affected neurons in the frontal cortex are tau negative. Instead they have intranuclear and cytoplasmic ubiquitinated and TDP-43 positive inclusions. In addition rare VCP positive intranuclear inclusions are present.
More information on our research can be found on the Weihl Lab website.