Biology subjects

Tolve, M.

Publications and source records attributed to Tolve, M..

4 recordsLinked to original sources

bioRxiv2024

Autophagy regulator ATG5 preserves cerebellar function by safeguarding its glycolytic activity

Dysfunctions in autophagy, a highly conserved cellular mechanism responsible for the degradation of intracellular components within lysosomes, often result in neurodegeneration. The neuroprotective effect of autophagy varies across neuronal subtypes, and the mechanisms of selective vulnerability of neurons to autophagy dysfunction are currently unknown. Utilizing a mouse model of ATG5 deficiency in inhibitory neurons and a comprehensive approach, including PET imaging, metabolomics, stable-isotope labeling studies, and live cell imaging, we establish that autophagy contributes to the survival of cerebellar Purkinje cells (PCs) by safeguarding their glycolytic activity. We show that the core autophagy protein ATG5 downregulates the levels of the glucose transporter 2 (GLUT2) during brain maturation. Autophagy-deficient PCs exhibit increased glucose uptake, along with elevated levels of glycolytic intermediates and methylglyoxal-modified proteins. We propose lysophosphatidic acid and serine as glycolytic intermediates inducing PC death and demonstrate that deletion of GLUT2 in ATG5-deficient mice mitigates PC neurodegeneration and restores their ataxic gait. Taken together, this study reveals a novel neuroprotective role of autophagy in preventing excessive glycolytic metabolism in the brain.

neuroscience↗

bioRxiv2023

Functional convergence underground? The scale-dependency of community assembly processes in European cave spiders

Understanding how species assemble into communities is a central tenet in ecology. One of the most elusive questions is the relative contribution of environmental filtering versus limiting similarity. Important advances in this area have been achieved by looking at communities through a functional lens (i.e., the traits they express), so as to derive principles valid across species pools. Yet, even using traits in lieu of taxonomy, the issue remains controversial because i) environmental filtering and limiting similarity often act simultaneously in shaping communities; and ii) their effect is scale-dependent. We exploited the experimental arena offered by caves, island-like natural laboratories characterized by largely constant environmental gradients and a limited diversity of species and interactions. Leveraging uniquely available data on distribution and traits for European cave spiders, we tested explicit hypotheses about variations in community assembly rules across ecological gradients and scales. We demonstrate that environmental filtering and limiting similarity shape cave communities acting on trait evolution in opposing directions. These effects are strongly scale dependent, varying along multiple environmental gradients. Conversely, the effect of geography on trait composition is weak, indicating that trait turnover in space happens primarily by substitution of species pursuing similar functions due to strong environmental filters. Our findings reconcile contrasted views about the relative importance of the two main mechanisms shaping patterns of biodiversity, and provide a conceptual foundation to account for scaling effects in the study of community assembly.

ecology↗

bioRxiv2022

Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling

Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, we show that the protein AuTophaGy 5 (ATG5) functions in neurons to regulate the cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of a synapse-confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA R1, which sequesters the PKA catalytic subunit and diminishes the cAMP/PKA-dependent phosphorylation of postsynaptic cytoskeletal proteins mediating AMPAR trafficking. Glutamatergic neurons-confined ATG5 deletion augments AMPAR-dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction.

neuroscience↗

bioRxiv2020

The transcription factor BCL11A defines a distinctive subset of dopamine neurons in the developing and adult midbrain

Midbrain dopaminergic (mDA) neurons are diverse in their projection targets, impact on behavior and susceptibility to neurodegeneration. Little is known about the molecular mechanisms that establish this diversity in mDA neurons during development. We find that the transcription factor Bcl11a defines a subset of mDA neurons in the developing and adult murine brain. By combining intersectional labeling and viral-mediated tracing we show that Bcl11a-expressing mDA neurons form a highly specific subcircuit within the dopaminergic system. We demonstrate that Bcl11a-expressing mDA neurons in the substantia nigra (SN) are particularly vulnerable to neurodegeneration in an -synuclein overexpression model of Parkinsons disease. Inactivation of Bcl11a in developing mDA neurons results in anatomical changes, deficits in motor learning and a dramatic increase in the susceptibility to -synuclein-induced degeneration in SN-mDA neurons. In summary, we identify an mDA subpopulation with highly distinctive characteristics defined by the expression of the transcription factor Bcl11a already during development.

developmental biology↗