[Pathophysiology of CADASIL disease]

Area of Science:

• Neurology
• Genetics
• Vascular Biology

Background:

• Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a well-characterized genetic disorder.
• The precise pathogenic mechanisms driving CADASIL remain incompletely understood.
• The Notch pathway's conservation facilitates the development of relevant animal and cellular models.

Purpose of the Study:

• To critically assess the validity of seven proposed pathogenic models for CADASIL.
• To explore the connection between vascular smooth muscle cell (VSMC) degeneration, ischemic lesions, and clinical manifestations.
• To discuss theories explaining the neurological predominance of this systemic arteriopathy.

Main Methods:

• Review and analysis of existing literature on CADASIL.
• Evaluation of seven distinct pathogenic models: autoimmune origin, mitochondrial dysfunction, Notch3 loss-of-function, GOM toxicity, and UPR activation.
• Discussion of VSMC degeneration, ischemic events, and symptom correlation.

Main Results:

• The review critically examines the strengths and limitations of each of the seven CADASIL pathogenic models.
• The relationship between VSMC pathology, ischemic lesions, and the resulting clinical symptoms is analyzed.
• The review highlights the systemic nature of CADASIL, despite its predominantly neurological presentation.

Conclusions:

• No single model fully explains CADASIL pathogenesis, necessitating further research.
• Understanding the interplay between VSMC dysfunction and neurological impact is crucial.
• CADASIL is a systemic vascular disease with specific neurological manifestations.