Tài liệu Báo cáo khoa học: Pharmacologic chaperoning as a strategy to treat Gaucher disease ppt

MINIREVIEW

Pharmacologic chaperoning as a strategy to treat Gaucher

disease

Zhanqian Yu, Anu R. Sawkar and Jeffery W. Kelly

Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA

Introduction

Human lysosomal storage diseases are loss of function

disorders, typically caused by a deficient lysosomal gly￾colipid hydrolysis activity, leading to intralysosomal

accumulation of the enzymes substrate(s) [1,2].

Although each lysosomal storage disease has unique

characteristics, generally they are progressive in nature

and lead to an enlarged liver and spleen, bone and

skeletal changes, short stature and respiratory and ⁄ or

cardiac problems.

Gaucher disease (GD) is caused by deficient lyso￾somal glucocerebrosidase (GC or acid b-glucosidase)

activity [3,4]. Glucocerebrosidase degrades glucosylcer￾amide (Fig. 1) into glucose and ceramide, which are

recycled in the cytoplasm. Mutations in both alleles of

GC sometimes result in the accumulation of glucosyl￾ceramide in the lysosomes of monocyte-macrophage

cells, often leading to hepatomegaly, splenomegaly,

anemia and thrombocytopenia, bone lesions, and some￾times central nervous system (CNS) involvement [5,6].

Patients not exhibiting CNS symptoms are classified as

type 1, whereas the 4% of patients presenting with

CNS involvement are classified as either type 2 (acute

infantile) or type 3 (juvenile or early adult onset).

Of the 200 mutations associated with GD, only a

few are prominent. For example, over 70% of the vari￾ant alleles among the Ashkenazi Jewish subjects are

N370S (Fig. 2B) [5,7–9]. The neuropathic L444P allele

occurs at a much higher frequency (37.5%) among

non-Jewish subjects (Fig. 2B). GD is recessive, mean￾ing that patients require mutations in both GC alleles

to present with symptoms and, even then, the pene￾trance is variable, suggesting that physiological and

Keywords

endoplasmic reticulum-associated

degradation; folding; Gaucher disease;

neuropathic Gaucher disease; pharmacologic

chaperone; traficking; type 2 Gaucher

disease; type 3 Gaucher disease

Correspondence

J. W. Kelly, Department of Chemistry and

The Skaggs Institute for Chemical Biology,

The Scripps Research Institute, 10550 North

Torrey Pines Road, BCC265, La Jolla,

CA 92037, USA

Fax: +1 858 784 9610

Tel: +1 858 784 9880

E-mail: [email protected]

(Received 8 June 2007, accepted 8 August

2007)

doi:10.1111/j.1742-4658.2007.06042.x

We briefly introduce the most common lysosomal storage disorder, Gau￾cher disease, concisely describe the Food and Drug Administration

approved strategies to ameliorate Gaucher disease, and then outline the

emerging pharmacologic chaperone strategy that offers the promise to

remedy this malady.

Abbreviations

CNS, central nervous system; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; ERT, enzyme replacement

therapy; GC, glucocerebrosidase; GD, Gaucher disease; WT, wild type.

4944 FEBS Journal 274 (2007) 4944–4950 ª 2007 The Authors Journal compilation ª 2007 FEBS