Last edited: 9/11/2021

1. LYSOSOMES
Cell Biology | Lysosomes: Tay-Sachs, Fabry, Gaucher, Niemann- Medical Editor: Abigail S. Xu, RPh
Pick Disease

OUTLINE (i) Protein Folding

(ii) N-linked Glycosylation
I) FUNCTIONS OF LYSOSOMES
II) LYSOSOMAL STORAGE DISORDERS/ • Add mannose sugar in the amine end of the
SPHINGOLIPIDOSES protein via enzyme in the rough E.R.
III) REVIEW QUESTIONS
IV) REFERENCES (iii) Protein Packaging
• Package N-glycosylated protein into vesicle
(4) Protein Modifications in the Golgi Apparatus
COP II proteins
o Bind to protein-filled vesicles from the rough E.R. and
I) FUNCTIONS OF LYSOSOMES take the vesicles to the Golgi

(i) Phosphorylation
• Addition of phosphate group on the 6th carbon
of the mannose sugar glycosylated to the
protein
• USMLE question:
o I-cell Disease
 Defective phosphotransferase
 Golgi cannot add phosphate group to
mannose of proteins
• Phosphate group is needed for vesicle to bud
off from the Golgi and become lysosomes
• Without phosphorylation, functional lysosomal
enzymes will not be produced

(A) BREAKDOWN OF MACROMOLECULES VIA

ENDOCYTOSIS
Endocytosis
Brings macromolecules into cell
(1) Phagocytosis
Important in white blood cells (WBC)
o Macrophage
o Neutrophils
Engulf pathogens (i.e., bacteria)

o Special endosome
Figure 1. Summary of Functions of Lysosomes o Vesicle formed around a pathogen engulfed by
a phagocyte
SYNTHESIS OF LYSOSOMES
Protein synthesis
o Lysosomes contain enzymes, which are proteins
(1) Transcription o Proteases: breakdown proteins
DNA → mRNA o Nucleases: breakdown nucleic acids
Nucleus o Lipases: breakdown lipids
o Glucosidases: breakdown carbohydrates
(2) Translation
mRNA is transported out of the nucleus via nuclear pore
mRNA binds to ribosome
Ribosome begins translation of mRNA into protein
(3) Protein Modifications in the Rough E.R.
Ribosome is transported into the rough endoplasmic (2) Receptor-mediated endocytosis
reticulum (E.R.)
Translate mRNA to protein LDL (low-density lipoprotein)
Protein structure o Lipoprotein
o Amine end o bad cholesterol
o Carboxyl end LDL-Receptor
o Amino acids o Protein where LDL binds
o Location: Liver

Lysosomes CELL BIOLOGY: Note #1. 1 of 4

 (A) TAY-SACHS DISEASE

Endosome
o Contain LDL receptors and LDL molecules bound to it
o Also contain proton pumps that pumps in H+
 Acidic environment
 Make bond of LDL and LDL receptor weak
• LDL disassociate with LDL receptor
o Bubbled vesicle
 LDL and LDL receptor starts to separate and Figure 2. Summary of Pathophysiology and Manifestations of
move to opposite sides Tay-Sachs disease
o LDL and LDL receptors will move into two separate (1) Pathophysiology
vesicles
o Vesicle containing LDL ↓Hexaminidase-A enzyme
 Sent to lysosomes o Responsible for breaking down the macromolecule,
 Lysosomes contain lipases and GM2 Ganglioside
sphingomyelinases that can digest cholesterol, ↑↑↑GM2 Ganglioside
phospholipids, and proteins within the LDL Accumulation of GM2 ganglioside in tissues can cause
molecules damage to the affected tissue
 Breakdown of LDL molecules Autosomal recessive disorder
o Vesicle containing LDL receptor o Need two mutant copies of gene to express
 Sent back to cell membrane to be recycled
 Rebind to plasma membrane (2) Manifestations
 Next LDL can bind to the LDL receptor and repeat
the process of endocytosis
(i) Neurodegeneration
Secondary Lysosome • Primary site of accumulation of GM2
Formed after the lysosomes fuse with phagosomes/ ganglioside: Central Nervous System
endosomes • Hyperreflexia
o ↑Deep Tendon Reflexes (DTR)
(i) Release molecules into cytosol • Hyperacusis
o ↑hearing sensitivity
• Molecules can be used for some metabolic
pathways • Seizures
• Cherry Red Spots
(ii) Exocytosis o Accumulation in macula near the retina
• Lysosome goes to cell membrane (ii) No Hepatomegaly
• Bind to cell membrane
• Lysosomes are abundant in WBC and the
• Release molecules out of cell
liver (Recall: LDL receptors)
Summary • Tay-Sachs disease does NOT cause
Lysosomes break down macromolecules via the hepatomegaly unlike other lysosomal storage
hydrolytic enzymes through: disorders
o Phagocytosis • Tay-Sachs and Niemann-pick have similar
o Receptor-mediated endocytosis manifestations, but the major difference is
After breaking down the macromolecules, the there is no hepatomegaly in Tay-Sachs
molecules can be:
o Released into cytosol (B) FABRY’S DISEASE
o Released out of cell via exocytosis
(B) AUTOPHAGY OF ORGANELLES
Organelles (i.e., mitochondria, cytoskeleton, and other
proteins in the cell) reach their prime and wear out
Old organelles are tagged by creating a membrane
around them → autophagosome (a type of endosome)
Autophagosome is taken to lysosome
Lysosome break down the organelle
o Organelles contain macromolecules that can be
broken down by the hydrolytic enzymes Figure 3. Summary of Pathophysiology and Manifestations of
Fabry's Disease
II) LYSOSOMAL STORAGE DISORDERS/
(1) Pathophysiology
SPHINGOLIPIDOSES
α-Galactosidase deficiency
Lysosomes release hydrolytic enzymes that break down o α-Galactosidase breaks down ceramide trihexoside
macromolecules
o Lipase ↑↑↑ceramide trihexoside
o Protease o Accumulate in tissues
o Nuclease X-linked recessive
o Glucosidase o More common in males
o Other enzymes
Important!
Genetic conditions in which lysosomes are unable to
All lysosomal storage disorders are autosomal
break down macromolecules (High yield for USMLE) recessive except Fabry’s

2 of 4 CELL BIOLOGY: Note #1. Lysosomes

 (2) Manifestations “Mnemonic: FABRY-C” (D) NIEMANN PICK DISEASE

(i) Foamy urine

• Due to renal failure

(ii) Angiokeratoma
• Red spots on skin

(iii) Burning pain on hands and feet

• Indicative of neuropathy
Figure 5. Summary of Pathophysiology and Manifestations of
(iv) Really dry skin Niemann Pick Disease
• Hypohidrosis (1) Pathophysiology
o condition in which the person sweat less
than usual Autosomal recessive
↓Sphingomyelinase
(v) Y-chromosome o Sphingomyelinase breaks down sphingomyelin
• Only seen in males ↑↑↑Sphingomyelin
Similar manifestations to Tay-Sachs, but Niemann Pick
(vi) Cardiovascular disease causes Hepatomegaly, while Tay-Sachs does not

(C) GAUCHER’S DISEASE (2) Manifestations

Most common lysosomal storage disorder (i) Hepatosplenomegaly
• Enlargement of liver and spleen

(ii) Neurodegeneration
• Accumulation in brain
• Seizures
• Developmental delays
• Cherry red spot in macula of retina

(iii) Foam Cells

Figure 4. Summary of Pathophysiology and Manifestations of
Gaucher's Disease • Recall: Macrophages contain lysosome that
break down bacteria
(1) Pathophysiology
• Accumulation of sphingomyelin in
↓β-glucocerebrosidase (a.k.a. β-glucosidase) macrophages
↑↑↑glucocerebroside accumulation in tissues • ↑lipid inclusions in macrophages
Autosomal recessive
Difference between Gaucher cell and Foam Cell
(2) Manifestations
Substrate Accumulated
(i) Bone tissue accumulation o Gaucher: Glucocerebroside
o Foam: Sphingomyelin
a. Red bone marrow accumulation
• Damage Microscopy
o Gaucher: looks like crumpled tissue paper
• Pancytopenia
1. ↓RBC’s
2. ↓WBC’s
Table 1. Summary of the Lysosomal Storage Disorders
3. ↓platelets
Substrate
b. Bone accumulation Disease Enzyme Deficiency
Accumulated
• Bone infarction → bone crisis Tay-
• Avascular necrosis Hexaminidase A GM2 Ganglioside
Sachs
• Early-onset osteoporosis Ceramide
Fabry α-Galactosidase
o Continuous accumulation over time trihexoside
β-
(ii) Hepatosplenomegaly Gaucher Glucocerebroside
glucocerebrosidase
• Accumulation in the liver and spleen leading to Niemann
Sphingomyelinase Sphingomyelin
enlargement of the organ Pick
• Hepatomegaly: enlarged liver
• Splenomegaly: enlarged spleen
III) REVIEW QUESTIONS
(iii) Gaucher cells (high-yield USMLE question) 1) Rare inherited metabolic disorder that results from
• Recall: Macrophages contain lysosomes that defective phosphotransferase
breakdown bacteria and other a) Gaucher’s Disease
macromolecules b) I-cell disease
c) Fabry’s Disease
• Produced when glucocerebroside
d) Tay-Sachs Disease
accumulate inside macrophages
• seen under microscopy
• Glucocerebroside is a type of lipid 2) Lysosomal storage disorder that does NOT cause
• ↑lipid inclusions in macrophages hepatomegaly
• Accumulate in the bones, liver, and spleen a) Niemann-Pick Disease

Lysosomes CELL BIOLOGY: Note #1. 3 of 4

 b) I-cell disease
c) Fabry’s Disease
d) Tay-Sachs Disease

3) X-linked Sphingolipidosis
a) Niemann-Pick Disease
b) Gaucher’s disease
c) Fabry’s Disease
d) Tay-Sachs Disease

4) Which looks like crumpled tissue paper under

microscope?
a) I-cell
b) Macrophage
c) Gaucher cell
d) Foam cell

5) Which can lead to renal failure, manifesting as foamy

urine?
a) Niemann-Pick Disease
b) I-cell disease
c) Fabry’s Disease
d) Tay-Sachs Disease

CHECK YOUR ANSWERS

IV) REFERENCES
● Le T, Bhushan V, Sochat M, Chavda Y, Zureick A. First Aid for
the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017
● Marieb EN, Hoehn K. Anatomy & Physiology. Hoboken, NJ:
Pearson; 2020.
● Boron WF, Boulpaep EL. Medical Physiology.; 2017.
● Urry LA, Cain ML, Wasserman SA, Minorsky PV, Orr RB,
Campbell NA. Campbell Biology. New York, NY: Pearson; 2020.

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