Topic Overview:
Degeneration of dopaminergic neurons in the substantia nigra (SN), a region of the midbrain, causes tremor, loss of spontaneous movement, and slowness.  The most common cause of this clinical syndrome is Parkinson’s disease.  However, other diseases, including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), also cause SN degeneration and similar movement problems.  Unlike PD, these disorders do not usually respond to Parkinson’s medications and result in severe disability and a greatly truncated lifespan.  PSP and MSA are collectively about a quarter as common as PD and are critically important problems in the clinical care of movement disorders patients.

In addition to cell loss and gliosis, many neurodegenerative diseases are characterized pathologically by inclusion body formation. In PSP, neurofibrillary tangles contain deposits of hyperphosphorylated Tau protein.  In MSA, glial cytoplasmic inclusions contain aggregated α-synuclein. Although involvement of these proteins in the pathogenesis of MSA and PSP is uncertain, an important role is strongly suggested by the finding that some cases of familial fronto-temporal dementia with clinical and pathological similarity to PSP result from mutations in the Tau gene.  Animal models in which abnormal forms or levels of Tau or α-synuclein are expressed in vivo show neurodegeneration, suggesting that abnormalities of these proteins could be central to pathogenesis.

Based on these findings, Burton wanted to create a model with true translational qualities, where discovery-driven research could identify appropriate therapeutic targets or candidate lead compounds for these diseases.  To this end, he has created zebrafish models of PSP and MSA by over-expressing different forms of Tau in neurons (PSP) or α-synuclein in glia (MSA).   Zebrafish are well-suited for high-throughput screening of compounds, a critical step for drug discovery.  But an important question is whether the zebrafish provides an appropriate model for these diseases. 

Preliminary results in Burton’s laboratory have begun to confirm the model’s validity.  Zebrafish with Tau or α-synuclein overexpression show movement abnormalities and biochemical changes similar to those found in corresponding human diseases.  In order to use the models as tools for drug and gene discovery, Burton and colleagues have developed software to conduct behavioral analysis of larval zebrafish in 96-well plates and also new transgenic zebrafish lines, allowing in vivo dopamine neuron visualization. 

Burton’s use of a zebrafish model to dissect the role of Tau and α-synuclein proteins in neurodegenerative diseases will potentially allow him to identify therapeutic targets and candidate drug compounds.  This powerful modeling technique could shave years off of the time required to find an appropriate treatment for these devastating conditions, thus improving patient outcomes much sooner than traditional methods allow.