Biology subjects

Prochiantz, A. L.

Publications and source records attributed to Prochiantz, A. L..

3 recordsLinked to original sources

bioRxiv2024

ALS driven by mutant NEK1 aggregation is accelerated by Pml loss, but clinically reversed through pharmacologic induction of Pml-mediated degradation

Germinal mono-allelic loss-of-function mutations of NEK1 drive Amyotrophic Lateral Sclerosis (ALS) at variable penetrance, presumably through haploinsufficiency. Modeling the ALS-associated Arg812Ter mutation in mice revealed that the resulting truncated Nek1 (Nek1t) is aggregation-prone, particularly in alpha-motoneurons (MNs), and drives canonical ALS symptoms when bi-allelically expressed (Nek1t/t). Promyelocytic leukemia (Pml) ablation allows for ALS symptoms to occur even in heterozygote Nek1wt/t animals, mimicking the human situation. Pml precludes disease occurrence by promoting SUMO-facilitated degradation of Nek1t proteins through PML nuclear bodies (NBs). Conversely, Pml induction, achieved by activating the interferon pathway via poly(I:C) treatment, clears Nek1t aggregates in MNs, dramatically reducing ALS-associated symptoms and extending survival by 5 months. Our studies highlight the role of NEK1 aggregates in ALS pathogenesis and identifies activation of interferon pathways as a candidate therapeutic strategy that not only promotes Pml-triggered SUMOylation/degradation of toxic misfolded proteins in vivo, but also facilitates the clearance of protein aggregates, yielding dramatic clinical improvement. These observations validate PML as a relevant therapeutic target in neurodegenerative conditions associated with protein aggregation.

pathology↗

bioRxiv2020

OTX2 non-cell autonomous activity regulates inner retinal function

OTX2 is a homeoprotein transcription factor expressed in photoreceptors and bipolar cells in the retina. OTX2, like many other homeoproteins, transfers between cells and exerts non-cell autonomous effects such as promoting survival of retinal ganglion cells that do not express the protein. Here we used a genetic approach to target extracellular OTX2 in the retina by conditional expression of a secreted single chain anti-OTX2 antibody. Compared to control mice, the expression of this antibody by Parvalbumin-expressing neurons in the retina is followed by a reduction in visual acuity in one-month-old mice with no alteration of the retinal structure or cell type number or aspect. A- and b-waves measured by electroretinogram were also indistinguishable from control mice, suggesting no functional deficit of photoreceptors and bipolar cells. Mice expressing the OTX2-neutralizing antibody did show a significant doubling in the flicker amplitude, consistent with a change in inner retinal function. Our results show that interfering in vivo with OTX2 non-cell autonomous activity in the postnatal retina leads to an alteration in inner retinal cell functions and causes a deficit in visual acuity. Significance statementOTX2 is a homeoprotein transcription factor expressed in retinal photoreceptors and bipolar cells. Although the Otx2 locus is silent in the inner retina, the protein is detected in cells of the ganglion cell layer consistent with the ability of this class of proteins to transfer between cells. We expressed a secreted single chain antibody (scFv) against OTX2 in the retina to neutralize extracellular OTX2. Antibody expression leads to reduced visual acuity with no change in retinal structure, or photoreceptor or bipolar physiology; however, activity in the inner retina was altered. Thus, interfering with OTX2 non-cell autonomous activity in postnatal retina alters inner retinal function and causes vision loss, highlighting the physiological value of homeoprotein direct non-cell autonomous signaling.

neuroscience↗

bioRxiv2019

The homeoprotein ENGRAILED-1 promotes motoneuron survival and sustains motor functions

Motoneuron degeneration leads to skeletal muscle denervation and impaired motor functions, yet the signals involved remain poorly understood. We find that extracellular ENGRAILED-1, a homeoprotein expressed in spinal cord V1 interneurons that synapse on -motoneurons, has non-cell autonomous activity. Mice heterozygote for Engrailed-1 develop muscle weakness, abnormal spinal reflex and partial neuromuscular junction denervation. A single intrathecal injection of ENGRAILED-1 restores innervation, limb strength, extensor reflex and prevents lumbar -motoneuron death for several months. The autophagy gene p62, which was found to network with Engrailed-1 and amyotrophic lateral sclerosis genes, is misregulated in Engrailed-1 heterozygote mice -motoneurons and is rescued following ENGRAILED-1 injection. These results identify ENGRAILED-1 as an -motoneuron trophic factor with long-lasting protective activity.

neuroscience↗