STUDY OF TDP-43 GENETIC AND PROTEIN-BASED INTERACTIONS: FOCUS ON ALZHEIMER AND PARKINSON?S DISEASES GENE PRODUCTS

GEREZ J; IGAZ LM; PRYMACZOK NC

Buenos Aires

Congreso; 2nd FALAN (Federation of Latin American and Caribbean Neurosciences) Congress; 2016

FALAN (Federation of Latin American and Caribbean Neurosciences)

 When a protein misfolds and evades normaldegradation pathways, a pathogenic process can arise in which proteinaggregates progressively assemble into toxic intra- or extra-cytoplasmic inclusions.In Alzheimer (AD) and Parkinson?s disease (PD), neuronal inclusions are accompaniedby massive cell death. Similarly, TDP-43 inclusions are a hallmark offrontotemporal lobar degeneration (FTLD-TDP) and amyotrophic lateral sclerosis(ALS), two neurodegenerative disorders with genetic, clinical and pathologicaloverlap. TDP-43 is normally a nuclear protein whose aggregation and mislocalizationlead to FTLD and ALS. AD/PD and FTLD/ALS might be pathologically linked;dementia as well as parkinsonism are found in approximately 30% of patientswith FTLD/ALS, and TDP-43 aggregates containing Amyloid-beta or alpha-synucleincan be found in such diseases. Although protein aggregation might be the linkbetween AD/PD and FTLD/ALS, the molecular mechanisms of such interaction areunknown. Using biochemistry approaches and live cell and confocal microscopy wefound that TDP-43 is affected by specific genes involved in AD and PDpathogenesis. Preliminary results indicate that changes in TDP-43 might be due tostructural alterations as well as its mislocalization. Ongoing in vivo studies in mice will shed lightinto the pathophysiological relevance of these interactions. Our data might helpunderstand the molecular mechanisms underlying the co-occurrence of dementiaand parkinsonism in FTLD/ALS.