Neuronal Ceroid Lipofuscinosis-Concepts, Classification, and Avenues for Therapy

Abstract

Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative lysosomal storage disorders characterized by excessive accumulation of lysosomal lipofuscin. Thirteen subtypes of NCL have been identified, each associated with distinct genes encoding various transmembrane proteins, secretory proteins, or lysosomal enzymes. Clinically, NCL manifests in infants through vision impairment, motor and cognitive dysfunctions, epilepsy, and premature death. The pathological complexity of NCL has hindered the development of effective clinical protocols. Current treatment modalities, including enzyme replacement therapy, pharmacological approaches, gene therapy, and stem cell therapy, have demonstrated limited efficacy. However, emerging evidence suggests a significant relationship between NCL and microglial cells, highlighting the potential of novel microglial cell replacement therapies. This review comprehensively examines the pathogenic genes associated with various NCL subtypes, elucidating their roles, clinical presentations, and corresponding mouse models. Especially, we thoroughly discuss the advances in the clinical study of potential therapeutics, which crucially calls for early diagnosis and treatment more than ever.

Keywords: enzyme replacement therapy; lysosomal storage disorders; microglial cell replacement therapies; neuronal ceroid lipofuscinosis.

FIGURE 1 |

The locations of NCL proteins. CLN1 (PPT1), CLN2 (TPP1), CLN10 (CTSD), and CLN13 (CTSF) encodes soluble NCL proteins with known enzymatic activity; CLN4 (DNAJC5), CLN5, CLN11 (GRN), and CLN14 (KCTD7) encodes soluble proteins with one protein (encoded by GRN) localized to compartments in the secretory pathway; CLN3, CLN6, CLN7 (MFSD8), CLN8, and CLN12 (ATP13A2) encodes transmembrane proteins with different subcellular locations: CLN3 mainly localizes to the plasma membrane, Golgi, endosome and lysosome; CLN6 localize to the ER; MFSD8 mainly localize to the lysosome and endosome; CLN8 shuttles between the ER and the ERGIC compartment; ATP13A2 mainly localize to the membrane of lysosomes and late endosomes.