Research Goals

We investigate the molecular mechanisms underlying tauopathies (Alzheimer’s disease and related dementias) and Parkinson’s disease, integrating genetic studies in patients with experimental models. Using transgenic mice and cultured neurons, we examine neuronal dysfunction, survival, and death, and evaluate candidate molecular therapies for neurodegenerative processes. In particular, we develop and validate RNA-based therapeutic tools, such as artificial microRNAs, to selectively modulate gene expression. By combining insights from human genetics, animal models, and cell-based systems, our goal is to uncover key pathways of neuronal vulnerability and advance innovative therapeutic strategies. We pursue these aims through three main lines of research:

Post-transcriptional regulation of tau
This project focus on understanding the post-transcriptional regulation of the MAPT gene, which encodes the microtubule-associated protein tau, and on evaluating the functional consequences of its alterations in models of neurodegeneration. Tau is predominantly expressed in neurons, where it contributes to microtubule stabilization and axonal transport under normal conditions. Alzheimer’s disease (AD) and related neurodegenerative disorders are classified as tauopathies due to the abnormal accumulation of tau protein in affected brains.
In our laboratory, we pioneered and optimized a molecular strategy to correct defects arising from abnormal tau splicing through the expression of heterologous RNA fragments capable of coupling with the endogenous transcript to generate functional RNA chimeras (Avale et al., 2013). This trans‑splicing approach allowed us to study the consequences of tau isoform imbalance on axonal transport in human neurons (Lacovich et al., 2017), the development of cognitive deficits in a murine tauopathy model (Espindola et al., 2018), and motor deficits related to parkinsonism (Damianich et al., 2021). We further refined this trans‑splicing intervention for phenotypic rescue in a preclinical model (Muñiz et al., 2022).
To expand therapeutic applications, we also developed novel RNA-based tools, including artificially designed microRNAs (Facal et al.2024, 2025), to silence tau and evaluate phenotypic recovery. This work is currently being complemented by ongoing studies on the selective vulnerability of neuronal populations in tauopathies and Parkinson’s disease, aiming to uncover the molecular bases of neuronal susceptibility and to advance targeted therapeutic strategies.

Predictive phenotypes and environmental effects in the development of tauopathies
To gain deeper insight into prodromal phenotypes and advance early diagnosis of dementias, we investigate early biochemical, behavioral, and sensory markers that may predict neurodegenerative processes associated with tau dysfunction and/or other target molecules. We also explore environmental factors that could influence the development and progression of tau pathology.
Our studies examine how specific conditions—such as sleep disturbances, olfactory impairment, hearing loss, exposure to synthetic or natural compounds, and dietary habits—affect pathological tau accumulation and modulate the manifestation of early or late phenotypes in tauopathy models.

GWAS Analysis and Translational Research
Our laboratory is part of the Argentine Consortium for Translational Research in Primary Tauopathies (CAITauP), which aims to establish a comprehensive repository of clinical, genetic, molecular, and histopathological data from patients with Progressive Supranuclear Palsy (PSP) and corticobasal degeneration (CBD) in Argentina. This resource enables us to perform genome-wide association studies (GWAS) to identify genetic variants linked to these disorders and to translate these findings into mechanistic insights and potential therapeutic approaches. (https://ingebi-conicet.gov.ar/en/caitaup-en/)