Disorders Resulting froDisorders Resulting from Defects in Lysosomal m Defects in Lysosomal

FunctionFunction

Characteristics of Lysosomes

Lysosome is a heterogenous organelle （异质性细胞器） :Primary lysosome （初级溶酶体）Second lysosomes （次级溶酶体） heterophagic

（异噬溶酶体） autophagic

（自噬溶酶体）Residual body

（残余小体）

Primary Lys

Second Lys

The Functions of Lysosomes

Lysosomes are involved in three major cell functions:

① phagocytosis （吞噬）

A summary of the phagocytic pathway

② autophagy （自吞）

Electron micrograph of a mitochondrion and peroxisome( 过氧化物酶体 )enclosed in a double membrane wrapper derived from the ER.This autophagic vacuole would have fused with a lysosome and its contents digested.

③ endocytosis （内吞作用）

Disorders Resulting from Defects in lysosomal FunctionDisorders Resulting from Defects in lysosomal Function

• I-cell disease :

Many cells in these patients contain lysosomes that are bloated with undergraded materials.

When fibroblasts from these patients were studied in culture ,it was found that lysosomal enzymes are synthesized at normal levels but are secreted into the medium and not targeted to lysosomes.

The I-cell defect was soon traced to the deficiency of an enzyme(N-acetyglucosamine phosphotransferase)required for mannose phosphorylation.

The secreted enzymes lacked the mannose phosphate residue that are present on the corresponding enzymes of cells from normal individuals.

Pompe diseasePompe disease: : a fatal inherited conditiona fatal inherited condition

in the absence ofα-glucosidase ,undigested glycogen in the absence ofα-glucosidase ,undigested glycogen accumulated in lysosomes,causing swelling of the organaccumulated in lysosomes,causing swelling of the organelles and irreversible damage to the cells and tissueselles and irreversible damage to the cells and tissues

Diseases of this type, characterized by the deficiency of a sDiseases of this type, characterized by the deficiency of a single lysosomal enzyme and the corresponding accumulingle lysosomal enzyme and the corresponding accumulation of undergraded substrate,are called ation of undergraded substrate,are called lysosomal stolysosomal storage diseasesrage diseases

Other Other lysosomal storage diseaseslysosomal storage diseases

DiseaseDisease Enzyme Enzyme DeficiencyDeficiency

Principle Storage Principle Storage substancesubstance

consequencesconsequences

GGM1M1 Gangliosi Gangliosid-osisd-osis

GM1 β-GalactoGM1 β-Galactosidasesidase

Ganglioside GGanglioside GM1M1 Mental retardation,liver enlargemeMental retardation,liver enlargement,skeletal involvement,death by ant,skeletal involvement,death by age 2 ge 2

Tay-Sachs diTay-Sachs dieaseease

HexosaminidasHexosaminidase Ae A

Ganglioside GGanglioside GM2M2 Mental retardation,blindness,death Mental retardation,blindness,death by age 3by age 3

Fabry’s diseaFabry’s diseasese

α-Galactosidasα-Galactosidase Ae A

TrihexosylceramiTrihexosylceramidede

Skin rash,kidney failure,pain in lowSkin rash,kidney failure,pain in lower extremitieser extremities

Sandhoff’sdisSandhoff’sdiseaseease

HexosaminidasHexosaminidase A and Be A and B

Ganglioside GGanglioside GM2 M2

and globosideand globosideSimilar to Tay-Sachs diease but mSimilar to Tay-Sachs diease but more rapidly progressingore rapidly progressing

Gaucher’s disGaucher’s diseaseease

GlucocerebrosiGlucocerebrosidasedase

GlucocerebrosideGlucocerebroside Liver and spleen enlargement,erosLiver and spleen enlargement,erosion of long bones,mental retardatioion of long bones,mental retardation in infantile form onlyn in infantile form only

Tay-Sachs diseaseTay-Sachs disease: : the best –studied lysosomal storathe best –studied lysosomal storage diseasesge diseases

It results from a deficiency of the enzyme β-N-hexosaminidasIt results from a deficiency of the enzyme β-N-hexosaminidase A, an enzyme that degrades the ganglioside Ge A, an enzyme that degrades the ganglioside GM2M2

GGM2M2 is a major component of the membranes of brain cells , is a major component of the membranes of brain cells ,and in the absence of the hydrolytic enzyme ,the ganglioside and in the absence of the hydrolytic enzyme ,the ganglioside accumulates in the bloated lysosomes of brain cells,causing accumulates in the bloated lysosomes of brain cells,causing dysfunctiondysfunction

In its severe form ,which strikes during infancy ,the disease iIn its severe form ,which strikes during infancy ,the disease is chacterized by progressive mental and motor retardation, as chacterized by progressive mental and motor retardation, as well as skeletal ,cardiac,and resiratory abnormalitiess well as skeletal ,cardiac,and resiratory abnormalities