PCSK9 deficiency promotes the development of peripheral neuropathy

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein receptor (LDLR) levels, impacting blood LDL-cholesterol.
• PCSK9 exhibits pleiotropic effects beyond lipid metabolism, influencing inflammation, infection, and cancer.
• The role of PCSK9 in peripheral nerve function and lipid homeostasis is currently unknown.

Purpose of the Study:

• To investigate the impact of PCSK9 deficiency on the peripheral nervous system.
• To elucidate the mechanisms by which PCSK9 influences nerve structure and function.

Main Methods:

• Utilized a mouse model with PCSK9 gene deletion (PCSK9 knockout mice).
• Assessed sensory perception (thermal and mechanical pain), nerve histology, and molecular markers in peripheral nerves.
• Analyzed lipid content, mitochondrial structure, and acylcarnitine profiles in nerve tissues.

Main Results:

• PCSK9 deficiency led to peripheral neuropathy, evidenced by reduced pain sensitivity.
• Histological analysis revealed decreased nociceptive Schwann cells, axonal swelling, and hypomyelination in PCSK9-deficient mice.
• Upregulation of CD36, increased nerve lipid content, mitochondrial abnormalities, and acylcarnitine accumulation were observed.

Conclusions:

• PCSK9 plays a significant role in maintaining peripheral nerve integrity and lipid homeostasis.
• PCSK9 deficiency results in peripheral neuropathy with distinct structural and metabolic alterations.
• These findings highlight a novel function of PCSK9 in the nervous system.