Achucarro Seminars

22 Dec [2017]

at 13.00 CET

Synaptic dysfunction and neuronal plasticity in motor and cognitive alterations in Huntington's disease: therapeutic perspectives

Jordi Alberch

Department of Biomedicine, Medical School, Institute of Neuroscience. University of Barcelona IDIBAPS. CIBERNED


Huntington's disease (HD) is neurodegenerative disorders with motor and cognitive alterations caused by a polyglutamine expansion in the protein huntingtin. It is characterized by intraneuronal inclusions and selective death of striatal projection neurons and cortical neurons. In research, most of the emphasis has been on understanding the cell death and its mechanisms. Until recently, it was believed that the vast majority, if not all, of the symptoms in HD are a direct consequence of neurodegeneration. However, increasing evidence shows that subtle alterations in synaptic function could underlie the early symptoms. It is of particular interest to understand the nature of this neuronal dysfunction for developing neuroprotective treatments.

Different studies in our lab have identified several mechanisms involved in the modulation of neuronal plasticity affected by mutant huntingtin in striatal, cortical or hippocampal neurons. The neurotrophic regulation of the BDNF/TrkB/p75 system is critical in the maintenance of the corticostriatal pathway playing a key role in the neuronal dysfunction induced by mutant huntingtin. Thus, drugs that regulate the release of endogenous BDNF, TrkB agonists or modulators of the imbalance of TrkB and p75 can be used as therapeutic agents for HD.

BDNF is also important in the maintenance of neuronal connectivity modulating NMDA receptors. Mutant huntingtin disturbs the excitatory/inhibitory imbalance that produces an aberrant function of NMDA receptors. Different studies in HD models show that neuronal dysfunction and behaviour can be recovered decreasing Glu3A receptors or increasing Pyk2, a non-receptor calcium-dependent protein-tyrosine kinase, which is associated with alterations in NMDA receptors, PSD-95 and dendritic spines.

Therefore, the search for new treatments for HD must be focussed to keep the integrity of neuronal connectivity, identifying mechanisms and intracellular pathways activated by mutant huntingtin that modulate synaptic activity and neuronal dysfunction.

Activity partially supported by UPV/EHU.

Host: Carlos Matute