Disorders Resulting from Defects in Lysosomal Function

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Disorders Resulting from Defects in Lysosomal
Function

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The function of Lysosomes

• Lysosomes are involved in three major cell
  functions
• 1).phagocytosis(??)
• 2).autophagy(??)
• 3).endocytosis(????)
• Lysosomes are an animal cell's digestive
  organelles ,their total enzymes can hydrolyze
  virtually every type of biological macromolecule.

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Diseases resulting from defects in lysosomal
function

• I-cell disease (I-???)
• Lysosomal storage diseases (??????)

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I-cell disease

• Caused by the deficiency of an enzyme(N-acetygluco
  samine phosphotransferase N-???????????)?Because
  of the absence of this enzyme,the secreted
  enzymes lack the mannose phosphate residues which
  is a signal for targeting lysosomal enzymes to
  lysosomes.
• Symptomsa rare inherited metabolic disorder
  characterized by coarse facial features,skeletal
  abnormalities and mental retardation .Many cells
  from these patients contain lysosomes that are
  bloated with undegraded materials.
  back

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Lysosomal storage diseases

• Characterized by the deficiency of a single
  lysosomal enzyme and corresponding accumulation
  of undegraded substance,for example these
  diseases resulting from an acumulation of
  undegraded sphingolipids.
• Pompe disease is also a type of Lysosomal storage
  diseases.

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• Pompe disease(???,????????), a hereditary
  metabolic disorder , result from the absence of
  a lysosomal enzyme, a-glucosidase(a-??????)whose
  absence will result in undigested glycogen
  accumulated in lysosomes.
• Symptomsaccumulation of glycogen in all
  organs,cardiorespiratory failure and death ,
  usually before age 2.

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Tay-Sachs disease(?-????)

• General situation
• The best-studied lysosomal storage diseases
• Incidence very rare in the general population
• 1 in 3600 newborns among Jews of eastern European
  ancestry
• Has dropped dramatically in this ethnic
  population in recent years

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Tay-Sachs disease(?-????)

• Cause
• Deficiency of the enzyme ß-N-hexosaminidase(?
  ???) A
• the ganglioside Gm2 accumulate in the
  bloated lysosomal of brain cells
• dysfunction

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Tay-Sachs disease(?-????)

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Tay-Sachs disease(?-????)

• Characterized
• Progressive mental and motor retardation
• Symptom
• Skeletal ,cardiac ,and abnormalities

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Tay-Sachs disease(?-????)

• Preventive
• Identification of carriers
• Genetic counseling of parents at risk
• Prenatal diagnosis by amniocentesis

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Treatment of lysosomal storage diseases

• Gauchers disease
• Accumulate large quantities of
  glucocerebroside lipids in the lysosomes of
  macrophages
• Spleen enlargement and anemia
• Attempt
• Enzyme replacement therapyalleviate
• Infusing a solution of the normal human
  enzyme into the bloodstreamthe enzyme was taken
  up by liver cellsunsuccessful

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Treatment of lysosomal storage diseases

• Effective treatment
• Purify the enzyme from human placental
  tissue
• treated with 3 different glycosidases to
  remove terminal sugars on the enzymes
  oligosaccharide chains expose
  mannose residues infusion into the
  bloodstream recognized by mannose
  receptor on the surface of macrophages
  taken up by endocytosis delivered to
  the natural target site in the cell where the
  deficiently is manifested
  

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Treatment of lysosomal storage diseases

• Clinical trials
• Enzyme replacement therapy
• Genetic therapy
• Marrow replanting therapy

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• Not everyone Lack a functional version of a
  particular protein is unable to synthesize that
  molecule.

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For example lysosomal storage diseases
There is a mutation with the diseases,which
destabilizes the encoded enzyme and caused it to
misfold. As we known ,misfold proteins are
recognized and destoryed . That is why these
patients lack the enzyme.
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• But what if it were possible to treat
  theses individuals with a substance that
  stablized the enzyme, allowing it to be
  transported out of the ER and into a lysosome?

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There is a clinical observation as follows

• Fabry disease is characterized by a deficiency of
  a-galactosidase A, an enzyme that degrades
  certain types of glycosphingolipids.
• One variant of Fabry disease leads specifically
  to heart disease.

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• In 2001,it is reported that a patient with Fabry
  disease whose heart was so damaged that he was
  awaiting a heart transplant.After three months of
  treatment with large quantities of the common
  monosaccharide galactose, his heart function had
  improved to the point that he was no longer a
  transplant candidate.
• Why?

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• Galactose is a competitive inhibitor of
  a-galactosidase A.
• competitive inhibition

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• So ,we can use the same strategy of administering
  a ligand that can bind and stablize a mutant
  protein to find a method for treating a variety
  of lysosomal stroage diseases and other types of
  congential diseases as well.

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• Moreover,enzyme binding compounds with low
  molecular mass can penetrate the blood-brain
  barrier . So maybe it can be used in prevent
  accumulation of undegrded materials in the brain.
  

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Thank you!
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