New research reveals the pathogenic mechanism of mutations in neuronal lipofuscinosis genes

Recently, the team of Professor Wang Hongyan of the Affiliated Obstetrics and Gynecology Hospital of Fudan University and the team of Wang Chenji, associate researcher of the College of Life Sciences, found that KCTD7 (a chromosomal gene) in neuronal lipofuscinosis was inactivated, interfering with the sorting and transport of lysosomal hydrolases, which in turn led to lysosomal functional defects and disease occurrence. The research has been published online in Science Advances.


The decrease in the efficiency of lysosomal enzyme sorting is illustrated by the respondent

Lysosomals have more than 60 acid hydrolases that digest a variety of specific biological macromolecules such as nucleic acids, proteins, lipids, and glycogen, which are essential for the recovery of damaged proteins and organelles, the maintenance of energy and metabolic homeostasis, and cell signaling. A growing body of research has found that abnormal lysosomal function leads to a range of metabolically related genetic disorders, known as lysosomal storage disorder (LSD). Neuronal waxy lipaxil axiosis (NCL) is the most abundant type of LSD. The clinical manifestations of the disease are progressive blindness, refractory epilepsy, progressive dyskinesia and early death, and due to severe clinical symptoms and extremely limited treatment options, NCL brings a heavy mental and economic burden to patients, families and society.

A total of 13 gene mutations have been found to cause NCL, most of which encode hydrolases positioned by lysosomals or regulatory proteins responsible for the transport of lysosomal enzymes from the endoplasmic reticulum to The Golgi and lysosomals. KCTD7 is the newly identified NCL pathogenic gene, but its physiological function and molecular mechanism of mutation pathogenesis are not well understood.

The researchers first constructed the cell line of KCTD7 gene knockout, and found that KCTD7-missing cells not only reproduced the patient’s unique electron microscopic dark osmium deposits and fingerprint-like characteristics, but also identified other serious phenotypes related to lysosomal defects, including abnormal accumulation of neutral lipid and glycogen particles, autophagy defects, decreased localization efficiency of lysosomal hydrolases in lysosomums, and significant increases in lysosomal-related cell death.

Subsequent studies have found that KCTD7 mediates the ubiquitination degradation of CLN5 ( a chromosomal gene ) , and in the case of excessive accumulation of CLN5 , the stoichiometry of the complex is abnormal , resulting in a decrease in the sorting efficiency of lysosomal enzymes from the endoplasmic reticulum to the Golgi apparatus.

In summary, the researchers revealed for the first time that KCTD7 plays a key role in the maintenance of protein homeostasis and lysosomal function, found that KCTD7 and CLN5, two NCL-related proteins, are biochemically related, and explained the pathological significance of KCTD7 mutations. The study also suggests that lowering CLN5 protein levels through drug targeting is a potentially targeted strategy for treating NCL subtypes of KCTD7 mutations. (Source: China Science Daily, Zhang Shuanghu, Huang Xin)

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