Lysosomes and Proteasomes

Discovered lysosomes

Christian de Duve

Centrifugation pellet components

mitochondria + lysosomes

Intact pellet - centrifugation

1. Respiratory activity

Injured pellet - centrifugation

1. Respiratory activity

2. Hydrolytic enzymatic activity (lysosomes)

Lysosome organelle, enzyme, maker enzyme, pH

1. single membrane

2. 50+ hydrolytic enzymes

3. pH 5

4. nucleases, phosphatase, ligases

5. marker enzyme - acid phosphatase

Diversity of lysosomes

1. Heterophagy

2. Autophagy

3. Specialized

Heterophagy

1 Lysosome - before fusion with late lysosome

2 Lysososme - after fusion with late lysosome

Rudolph Virchow

• pus

• WBC gives brith to RBC

Elie Metchnikoff

• phagocytosis

• Nobel prize 1908

• probiotics

Opsonization

pathogens/dead cells coated with opsonins (Ig antibodies aka Fc receptors) to make more visible/easily digested by phagocytes

Myasthenia Gravis

• autoimmune disease

• neuromuscular

• droopy eyelids

What is the basis for myasthenia gravis? 1950s

1. 1950s - acetylcholine neurochemical synapse

   1. Curare - blocks ACH-R, MG patients very sensitive

   2. Eseine (Neostigmine) - MG patients improve

What is the basis for myasthenia gravis? 1960s

MEPPs - miniature end plate potential

Normal: 2mv

MG: 1mv

What is the basis for myasthenia gravis? 1970s

alpha bungarotoxin - ultra structural autoradiography

• Too few ACH-Rs

• Electroplax - highest concentration of ACH-R

Treatment for myasthenia gravis

neostigmine - increase lifetime of acitase

prednisilone = decrease immune response

Vyvgart

Autophagy

1. mitochondria - half, 5-6 days (“mitophagy”)

2. peroxisomes = 1-2 days

Autophagy pathway

1. phagophore - initial autophagy

   1. emerges from RER

2. Autophagosome

3. Many dugs interfere with autophagy

   1. chloroquine

Specialized lysosomes

differentiated lysosomes

• acrosome

Lysosomal diseases

Non-genetic

inherited - lysosomal storage diseass

environmental

Silicosis - silica

• Fibrosis = collagen

• Lung is less elastic

• less co2/o2 exchange

Chloroquine myopathy/retinopathy

Inherited lysosomal storage diseases

to different lysosomal storage diseases

Treatment: ERT (enzyme replacement therapy)

Tay Sachs Disease

inherited lysosomal disease

• missing enzyme = Hex A

• Ganglioside GMZ accumulates in lysosomes

• No ERT yet

Hurlers Syndrome

Deficiency of the IDUA gene, leading to toxic buildup of sugar molecules (glycosaminoglycans) in cells

Basis for ERT

missing alpha-L iduronidase

Drug Alduasyne

I Cell Disease

I = inclusion disease

• lysosomes but without any hydrolytic enzymes

• Excess lysosomal enzymes outside cell

• can endocytose normal hydrolytic enzyme

• Normal fibroblasts can’t endocytose I cell lysosome enzymes

• Defect in N-acetylglucosamine pathway in cis Golgi

Gaucher disase

Deficiency in a-glucosidase

Gigantic lysosomes in muscle