Postdoctoral Seminars by Dr Juan Carlos Polanco & Dr Esteban Cruz Gonzalez - QBI

Speakers: 

Dr Juan Carlos Polanco 
Dr Esteban Cruz Gonzalez 
Clem Jones Centre for Ageing Dementia Research (CJCADR), Queensland Brain Institute
Queensland Brain Institute
University of Queensland

Title of first talk: Atlastin dysfunction linked to Tau pathology in Hereditary Spastic Paraplegia

Dr Juan Polanco

Hereditary Spastic Paraplegia (HSP) is a group of inherited neurological disorders characterized by progressive muscle stiffness and weakness in the legs, making walking difficult. HSP is caused by mutations in multiple genes, most commonly Spastin (SPAST) and Atlastin-1 (ATL1). These mutations disrupt key cellular processes, including intracellular transport, lipid metabolism, mitochondrial function, and intercellular communication, which is thought to ultimately drive axonal degeneration and the HSP pathology.

 
In vertebrates, Atlastin-1 belongs to a paralogous gene family comprising ATL1, ATL2, and ATL3. Notably, ATL2 expression is elevated in the brains of Alzheimer’s disease mouse models and patients (Han et al., 2021). Consistent with this, we recently identified ATL2 as a top regulator of Tau aggregation in a genome-wide CRISPRi screen (Polanco et al., 2023), implicating ATL2 in Tau pathology.

In my presentation, I will present functional evidence uncovering a mechanistic link between ATL1 and ATL2 in promoting Tau aggregate accumulation, a key pathogenic process in neurodegenerative brain diseases. In line with HSP being primarily associated with ATL1 mutations, overexpression of HSP-linked ATL1 variants robustly enhanced Tau aggregation in both Tau biosensor cells and primary mouse neurons. Together, these findings suggest that HSP may represent a previously underappreciated tauopathy, overlapping with movement disorders such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), as well as cognitive disorders including Alzheimer’s disease (AD). This notion aligns with prior studies reporting Tau accumulation in post-mortem Spastin-associated HSP brains (Wharton et al., 2003; White et al., 2000). We propose that the high prevalence of ATL1 and SPAST mutations in HSP may, at least in part, reflect their capacity to drive Tau pathology, thereby exacerbating neurodegeneration and disease severity.