Analysis of registered clinical trials in Italy regarding dermatology (2003-2022): a cross-sectional study on historical trend and prospects for industry investments.

Background: This cross-sectional analysis intends to evaluate trend and outlook of industry clinical research in Italy regarding dermatology and its prospects for the next few years.

Methods: A computerized search of ClinicalTrial.gov database was carried out considering the 20-year period 2003-2022 using the following string: "Skin Diseases OR Skin cancer OR Skin Neoplasms OR Skin Infection OR Skin Lesion OR Skin Ulcer OR Skin Laxity OR Skin toxicity OR Dermatologic Complication OR Skin abnormalities".

Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration.

Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the gene and mutations in the TANK-binding kinase 1 () gene. We found that TBK1 is phosphorylated in response to poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg→His) mutation in mice, poly(GA)-induced phenotypes were exacerbated.

Plasma PolyQ-ATXN3 Levels Associate With Cerebellar Degeneration and Behavioral Abnormalities in a New AAV-Based SCA3 Mouse Model.

Spinocerebellar ataxia type 3 (SCA3) is a dominantly inherited cerebellar ataxia caused by the expansion of a polyglutamine (polyQ) repeat in the gene encoding ATXN3. The polyQ expansion induces protein inclusion formation in the neurons of patients and results in neuronal degeneration in the cerebellum and other brain regions. We used adeno-associated virus (AAV) technology to develop a new mouse model of SCA3 that recapitulates several features of the human disease, including locomotor defects, cerebellar-specific neuronal loss, polyQ-expanded ATXN3 inclusions, and TDP-43 pathology.

HDAC6 Interacts With Poly (GA) and Modulates its Accumulation in c9FTD/ALS.

The aberrant translation of a repeat expansion in chromosome 9 open reading frame 72 (), the most common cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), results in the accumulation of toxic dipeptide repeat (DPR) proteins in the central nervous system We have found that, among the sense DPR proteins, HDAC6 specifically interacts with the poly (GA) and co-localizes with inclusions in both patient tissue and a mouse model of this disease (c9FTD/ALS). Overexpression of HDAC6 increased poly (GA) levels in cultured cells independently of HDAC6 deacetylase activity, suggesting that HDAC6 can modulate poly (GA) pathology through a mechanism that depends upon their physical interaction. Moreover, decreasing HDAC6 expression by stereotaxic injection of antisense oligonucleotides significantly reduced the number of poly (GA) inclusions in c9FTD/ALS mice.

poly(GR) aggregation induces TDP-43 proteinopathy.

TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by GC repeat expansions in the gene (c9FTD/ALS). Providing mechanistic insight into the link between mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded GC repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner to induce cytoplasmic TDP-43 inclusion formation.

Aberrant deposition of stress granule-resident proteins linked to C9orf72-associated TDP-43 proteinopathy.

Background: A GC hexanucleotide repeat expansion in the noncoding region of C9orf72 is the major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). Putative disease mechanisms underlying c9FTD/ALS include toxicity from sense GC and antisense GC repeat-containing RNA, and from dipeptide repeat (DPR) proteins unconventionally translated from these RNA products.

Methods: Intracerebroventricular injections with adeno-associated virus (AAV) encoding 2 or 149 GC repeats were performed on postnatal day 0, followed by assessment of behavioral and neuropathological phenotypes.