A large number of neurodegenerative diseases in humans result from protein misfolding and aggregation. Protein misfolding is believed to be the primary cause of Alzheimer's disease, Parkinson's disease, Huntington's disease, Creutzfeldt-Jakob disease, cystic fibrosis, Gaucher's disease and many other degenerative and neurodegenerative disorders. Cellular molecular chaperones, which are ubiquitous, stress-induced proteins, and newly found chemical and pharmacological chaperones have been found to be effective in preventing misfolding of different disease-causing proteins, essentially reducing the severity of several neurodegenerative disorders and many other protein-misfolding diseases. In this review, we discuss the probable mechanisms of several protein-misfolding diseases in humans, as well as therapeutic approaches for countering them. The role of molecular, chemical and pharmacological chaperones in suppressing the effect of protein misfolding-induced consequences in humans is explained in detail. Functional aspects of the different types of chaperones suggest their uses as potential therapeutic agents against different types of degenerative diseases, including neurodegenerative disorders.

https://febs.onlinelibrary.wiley.com/doi/epdf/10.1111/j.1742-4658.2006.05181.x

Protein‐misfolding diseases and chaperone‐based therapeutic approaches

This review covers the progress made in the chemistry, synthesis and biology of carbasugars until May 2004. It includes the extensively studied carbapyranoses as well as the scarcely considered carbafuranoses. Specific topics discussed include the natural occurrence of carbasugars, biosynthesis and biological activity of carbasugars, conformational analysis of carbasugars, and the compilation of synthetic methods of carbafuranoses and carbapyranoses.

Synthesis and conformational and biological aspects of carbasugars.

Gaucher disease (GD), an autosomal recessive disease, is characterized by accumulation of glucosylceramide mainly in cells of the reticuloendothelial system, due to mutations in the acid beta-glucocerebrosidase gene. Some of the patients suffer from neurological symptoms (type 2 and type 3 patients), whereas patients with type 1 GD do not present neurological signs. The disease is heterogeneous even among patients with the same genotype, implicating that a mutation in the glucocerebrosidase gene is required to cause GD but other factors play an important role in the manifestation of the disease. Glucocerebrosidase is a lysosomal enzyme, synthesized on endoplasmic reticulum (ER)-bound polyribosomes and translocated into the ER. Following N-linked glycosylations, it is transported to the Golgi apparatus, from where it is trafficked to the lysosomes. In this study, we tested glucocerebrosidase protein levels, N-glycans processing and intracellular localization in skin fibroblasts derived from patients with GD. Our results strongly suggest that mutant glucocerebrosidase variants present variable levels of ER retention and undergo ER-associated degradation in the proteasomes. The degree of ER retention and proteasomal degradation is one of the factors that determine GD severity.

/pdf/er-retention-and-degradation-as-the-molecular-basis-3vx6rx95mi.pdf

ER retention and degradation as the molecular basis underlying Gaucher disease heterogeneity

Identification and characterization of ambroxol as an enzyme enhancement agent for Gaucher disease.

Gaucher disease, the most common lysosomal storage disorder, is caused by the defective activity of the lysosomal enzyme, acid-beta-glucosidase (GlcCerase), leading to accumulation of glucosylceramide (GlcCer), particularly in cells of the macrophage lineage. Nearly 200 mutations in GlcCerase have been described, but for the most part, genotype-phenotype correlations are weak, and little is known about the down-stream biochemical changes that occur upon GlcCer accumulation that result in cell and tissue dysfunction. In contrast, the clinical course of Gaucher disease has been well described, and at least one treatment is available, namely enzyme replacement therapy. One other treatment, substrate reduction therapy, has recently been marketed, and others are in early stages of development. This review, after discussing pathological mechanisms, evaluates the advantages and disadvantages of existing therapies.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2141.2004.05351.x

Gaucher disease: pathological mechanisms and modern management.

N-octyl-beta-valienamine up-regulates activity of F213I mutant beta-glucosidase in cultured cells: a potential chemical chaperone therapy for Gaucher disease.

Enzyme enhancement activity of N-octyl -β -valienamine on β-glucosidase mutants associated with Gaucher disease

An acid addition salt of a carbasugar amine derivative represented by the following general formula (1): wherein R1 and R2 each independently represents hydrogen or an alkyl, alkenyl, alkynyl, acyl, aryl, or aralkyl group optionally having one or more substituents represented by the following (I) or (II), or R1 and R2 in combination represent a substituent represented by the following (III): (wherein R8 to R12 each independently represents alkyl, alkenyl, alkynyl, acyl, aryl, or aralkyl), provided that not both of R1 and R2 are hydrogen; R3, R4, and R7 each independently represents hydroxy or substituted hydroxy; and R5 and R6 each independently represents hydrogen, hydroxy, or substituted hydroxy, provided that when one of R5 and R6 is hydrogen, then the other is hydroxy or substituted hydroxy.

Miwa Sawa

Papers

N-octyl-beta-valienamine up-regulates activity of F213I mutant beta-glucosidase in cultured cells: a potential chemical chaperone therapy for Gaucher disease.

Enzyme enhancement activity of N-octyl -β -valienamine on β-glucosidase mutants associated with Gaucher disease

Acid addition salt of carbasugar amine derivative