Biology subjects

Kahn, B.

Publications and source records attributed to Kahn, B..

3 recordsLinked to original sources

bioRxiv2026

CDKL5 deficiency impairs TBK1-mediated autophagy and clearance of neuronal protein aggregates

The clearance of unwanted protein aggregates is essential for maintaining proteostasis and cellular function, particularly in long-lived cells such as neurons, yet the signaling pathways that activate selective autophagy of protein aggregates remain incompletely understood. Here, we identify the neurodevelopmental kinase CDKL5 as an upstream regulator of a signaling pathway involving the TBK1 adaptor SINTBAD and the selective autophagy receptors p62 and TAX1BP1. CDKL5-deficient mice show age-dependent accumulation of detergent-insoluble protein aggregates in the brain, accompanied by impaired TAX1BP1 recruitment and reduced p62 Ser405 phosphorylation. In cultured cells and primary cortical neurons, loss of CDKL5 delays clearance of puromycin- and proteasome-inhibitor-induced aggregates in a manner dependent on CDKL5 kinase activity. Mechanistically, CDKL5 kinase activity is required for SINTBAD Ser504 phosphorylation, a SINTBAD modification that promotes TBK1 activation, resulting in p62 Ser403/405 phosphorylation and TAX1BP1-dependent aggregate clearance. Phosphomimetic SINTBAD rescues these responses in CDKL5-deficient cells. These findings define a CDKL5/SINTBAD/TBK1 signaling axis that couples proteotoxic stress to activation of selective autophagy receptors and identify impaired proteostasis as a previously unrecognized consequence of CDKL5 deficiency.

physiology↗

bioRxiv2020

A selective projection from the subthalamic nucleus to parvalbumin-expressing interneurons of the striatum

The striatum and subthalamic nucleus (STN) are considered to be the primary input nuclei of the basal ganglia. Projection neurons of both striatum and STN can extensively interact with other basal ganglia nuclei, and there is growing anatomical evidence of direct axonal connections from the STN to striatum. There remains, however, a pressing need to elucidate the organization and impact of these subthalamostriatal projections in the context of the diverse cell types constituting the striatum. To address this, we carried out monosynaptic retrograde tracing from genetically-defined populations of dorsal striatal neurons in adult male and female mice, quantifying the connectivity from STN neurons to spiny projection neurons, GABAergic interneurons, and cholinergic interneurons. In parallel, we used a combination of ex vivo electrophysiology and optogenetics to characterize the responses of a complementary range of dorsal striatal neuron types to activation of STN axons. Our tracing studies showed that the connectivity from STN neurons to striatal parvalbumin-expressing interneurons is significantly higher (~ four-to eight-fold) than that from STN to any of the four other striatal cell types examined. In agreement, our recording experiments showed that parvalbumin-expressing interneurons, but not the other cell types tested, commonly exhibited robust monosynaptic excitatory responses to subthalamostriatal inputs. Taken together, our data collectively demonstrate that the subthalamostriatal projection is highly selective for target cell type. We conclude that glutamatergic STN neurons are positioned to directly and powerfully influence striatal activity dynamics by virtue of their enriched innervation of GABAergic parvalbumin-expressing interneurons.

neuroscience↗

bioRxiv2018

Thermoneutrality induces skeletal muscle myopathy via brown adipose tissue in an IRF4- and myostatin-dependent manner

Skeletal muscle and brown adipose tissue (BAT) share a common lineage and have been functionally linked, as exercise increases browning through the actions of various myokines. It is unknown, however, whether BAT can affect skeletal muscle function. Our prior work has shown that loss of the transcription factor IRF4 in BAT (BATI4KO) reduces adaptive thermogenesis. Here, we note that these mice also have reduced exercise capacity relative to wild-type littermates, associated with diminished mitochondrial function, ribosomal protein synthesis, and mTOR signaling in muscle, in addition to the signature ultrastructural abnormalities of tubular aggregate myopathy. Within brown adipose tissue, loss of IRF4 caused the induction of a myogenic gene expression signature, which includes an increase in the secreted factor myostatin, a known inhibitor of muscle function. Reduction of myostatin activity by the injection of neutralizing antibodies or soluble ActRIIB receptor rescued the exercise capacity of BATI4KO mice. Additionally, overexpression of IRF4 in brown adipocytes reduced serum myostatin and increased mitochondrial function and exercise capacity in muscle. A physiological role for this system is suggested by the observation that mice housed at thermoneutrality show lower exercise capacity with increased serum myostatin; both of these abnormalities are corrected by surgical removal of BAT. Collectively, our data point to an unsuspected level of BAT-muscle cross-talk driven by IRF4 and myostatin.\n\nHighlightsO_LIMice lacking IRF4 in BAT have a decrease in exercise capacity, accompanied by histological, ultrastructural, signaling, gene expression, and bioenergetic evidence of myopathy in white vastus.\nC_LIO_LILoss of IRF4 promotes the expression of a myogenic signature in BAT, including the myokine myostatin.\nC_LIO_LINeutralization of serum myostatin rescues the ability of BATI4KO mice to exercise normally, while overexpression of IRF4 in BAT allows mice to run better than wild-type counterparts.\nC_LIO_LIThermoneutrality reduces the level of IRF4 in BAT of WT mice, resulting in a myopathic phenotype that can be reversed by surgical excision of BAT.\nC_LI

physiology↗