Biology subjects

Baas, P. W.

Publications and source records attributed to Baas, P. W..

4 recordsLinked to original sources

bioRxiv2025

Analyses of exon 4a structure reveal unique properties of Big tau

Tau is a microtubule-associated protein that modulates the dynamic properties of microtubules and is involved in neurodegenerative diseases known as tauopathies. Tau is expressed as multiple low molecular weight (LMW) isoforms in most neurons of the central nervous system but only as a high molecular weight isoform in neurons of the peripheral nervous system and in a few types of central neurons. Big tau is defined by the inclusion of the alternatively spliced exon 4a, which adds about 250 amino acids to the domain of tau that projects away from the microtubule. Despite low sequence conservation of exon 4a, its length remains remarkably consistent across vertebrates. Here, we analyzed the charge distribution, hydrophobicity, and aggregation propensity of the human sequences of LMW tau, Big tau and the stretch of amino acids encoded by exon 4a. The exon 4a amino acids display a pronounced net negative charge (acidic/basic ratio = 1.30), a consistently hydrophilic composition (average Kyte-Doolittle score = -0.9259) and low {beta}-sheet content of 4.78%. This contrasts with LMW tau, which is more hydrophobic (-0.8930) and contains extended aggregation-prone motifs within the microtubule-binding domain including high {beta}-sheet content of 17.33%. The inclusion of exon 4a in Big tau shifts the global hydrophobicity to intermediate values (-0.9036) and reduces predicted {beta}-sheet content to 13.14%, suggesting decreased aggregation potential. Evolutionary analyses across mammals, birds, and amphibians (human, rat, zebra finch, frog) confirms the minimal sequence identity (16-24% identity in non-mammals) and conserved exon size but show preservation of net negative charge (acidic/basic ratio 1.3-2.3), indicating convergent retention of charge-based properties. Hydrophilicity was also broadly conserved, though less invariant across species. These results demonstrate that exon 4a introduces a highly acidic, hydrophilic module that counterbalances the aggregation-prone domains of LMW tau. The conservation of size and structural properties of the exon-4a-encoded stretch of amino acids, despite sequence divergence, implies strong evolutionary pressure to maintain biophysical properties that counteract pathogenic misfolding.

neuroscience↗

bioRxiv2025

Genotype-Phenotype Distinctions in Spastic Paraplegia 4 Reveal HDAC6 as a Therapeutic Target

Spastic Paraplegia 4 (SPG4) is the most prevalent form of Hereditary Spastic Paraplegia (HSP), a neurodegenerative disorder characterized by progressive lower limb spasticity and debilitating gait impairment, primarily driven by axonal degeneration of corticospinal motor neurons (CSMNs). Caused by mutations in the SPAST gene encoding spastin, an AAA-ATPase involved in microtubule severing and intracellular organelle function, SPG4 accounts for 40-50% of autosomal dominant HSP cases, yet without effective treatments. Although reduced microtubule acetylation has emerged as a key pathological mechanism, whether and how distinct mutations lead to microtubule deacetylation and subsequent neurodegeneration remains unclear. To address this, we generated isogenic human induced pluripotent stem cell (hiPSC) lines with two distinct heterozygous SPAST mutations - SPASTWT/C448Y (missense) and SPASTWT/S245X (truncation). Employing an innovative differentiation protocol, we created human motor cortical organoids enriched in CSMNs, providing a robust platform to study SPG4 pathophysiology. These organoids revealed striking genotype-phenotype distinctions, with mutation-specific variations in CSMN loss, axonal degeneration and neuronal activities, mirroring clinical heterogeneity. Mechanistic studies identified aberrant activation of histone deacetylase 6 (HDAC6), a major neuronal microtubule deacetylase, as a key driver of SPG4 pathology. This dysregulation was specifically attributed to mutant M1-spastin, the longer isoform of spastin. Remarkably, pharmacological inhibition of HDAC6 with Tubastatin A restored microtubule acetylation status and mitigated axonal degeneration in both SPAST-mutant organoids, with corresponding improvements in corticospinal tract integrity and gait deficits validated in SPG4-transgenic mice. Collectively, our study establishes isogenic hiPSC-derived motor cortical organoids as a robust human model for corticospinal motor neuron degeneration and identifies HDAC6 hyperactivation as a central pathogenic mechanism and viable therapeutic target in SPG4.

neuroscience↗

bioRxiv2024

Antagonistic Roles of Tau and MAP6 in Regulating Neuronal Development

Association of tau with microtubules causes them to be labile while association of MAP6 with microtubules causes them to be stable. As axons differentiate and grow long, tau and MAP6 segregate from one another on individual microtubules, resulting in the formation of stable and labile domains. The functional significance of the yin/yang relationship between tau and MAP6 remained speculative in those studies, with one idea being that such a relationship assists in balancing morphological stability with plasticity. Here, using primary rodent neuronal cultures, we show that depletion of tau has opposite effects compared to depletion of MAP6 on the rate of neuronal development, the efficiency of growth cone turning, and the number of processes and axonal branches. Opposite effects to those of tau depletion were also observed on the rate of neuronal migration, in an in vivo assay, when we depleted MAP6. When tau and MAP6 were depleted together in the cell culture assays, the morphological phenotypes negated one another. Tau and MAP6 are multifunctional proteins, but the present results suggest that the observed effects of their depletion on neuronal development are likely due to their opposite roles in regulating microtubule dynamics. SummaryTau and MAP6 play antagonistic roles in regulating multiple aspects of neuronal development, presumably via their antagonistic effects on microtubule dynamics.

cell biology↗

bioRxiv2023

ASD mutation of Katnal2 impairs ependymal ciliary motion and causes hydrocephalus

Katanin catalytic subunit A1 like 2 (KATNAL2) is a high-risk gene associated with autism spectrum disorders (ASD), however its impact on brain development and disease remains unclear. The present study revealed an unexpected role of KATNAL2 in regulating ependymal ciliary motion and cerebrospinal fluid flow during brain development, an important contributing factor for ASD. We discovered a distinct expression pattern of KATNAL2 in multiciliated ependymal cells of both human and mouse brains. Notably, an ASD-associated mutation of Katnal2 disrupted its molecular function and resulted in ASD-related behavioral deficits in mice. Additionally, this mutation affected the polarized organization and beating of ependymal cilia, leading to delayed cerebrospinal fluid flow and sustained ventricular enlargement from the early postnatal stage. Conditional ablation of Katnal2 specifically in the ependymal cells of neonatal mice is sufficient to cause ventricular dilation, whereas no such effect was observed in adult mice. Our findings highlight the importance of ependymal motile cilia and hydrocephalus in ASD, offering insights into its pathogenesis and potential intervention.

neuroscience↗