Subcellular Organelles Diseases

Dr. Nabeela Faisal

(Harper, Lippin, Internet, Marks)
Specific learning objectives
Explain the biochemical markers and importance of
subcellular organelles and their inherited disorders
especially:
1. I cell disease
2. Refsum disease
3. Parkinsonism
4. Progeria
 Subcellular organelles
• An organelle is a subcellular structure that has one or more
specific jobs to perform in the cell, much like an organ does
in the body.
• Among the more important cell organelles are the nuclei,
which store genetic information; mitochondria, which produce
chemical energy; and ribosomes, which assemble proteins.
Inherited disorders of
subcellular organelles
• Four well-defined groups of genetic diseases are recognized in
which the functions of an intracellular organelle are impaired:
• Lysosomal storage diseases,
• Mitochondrial disorders,
• Endoplasmic reticulum storage diseases, and
• Peroxisomal diseases
 Lysosomal storage diseases
• The health and survival of neurons in the brain is dependent
on lysosomes, cellular organelles that help degrade and
recycle proteins.
• Dysfunction of lysosomes, a critical component within
cells, plays a key role in the development of Alzheimer's
disease (AD).
• Alzheimer's disease and related dementias (AD/ADRD) are
debilitating conditions that impair memory, thought
processes, and functioning, primarily among older adults. The
effects of these diseases can be devastating, both for
individuals afflicted with AD/ADRD and for their families.
• A protein misfolding disease due to the accumulation of
abnormally folded amyloid beta (Aβ) protein in the brain.
 Lysosomal storage diseases
• Genetic defects in lysosomal enzymes, or in proteins such as the
mannose- 6-phosphate receptor required for targeting the enzymes
to the lysosome, lead to an abnormal accumulation of undigested
material in lysosomes that may be converted to residual bodies.
• The accumulation may be so extensive that normal cellular
function is compromised, particularly in neuronal cells.
• Genetic diseases such as Tay-Sachs disease (an accumulation of
partially digested gangliosides in lysosomes), and
• Pompe disease (an accumulation of glycogen particles in
lysosomes) are caused by the absence or deficiency of specific
lysosomal enzymes.
• Such diseases, in which a lysosomal function is compromised, are
known as lysosomal storage diseases.
• (Marks)
 I-cell disease
• I-cell disease (mucolipidosis II) is a rare inherited metabolic
disorder characterized by coarse facial features, skeletal
abnormalities and mental retardation.
• The symptoms of I-cell disease are similar to but more severe
than those of Hurler syndrome.
Pathophysiology of I-cell
disease
I-cell disease is an autosomal recessive disorder caused by a
deficiency of GlcNAc phosphotransferase, which
phosphorylates mannose residues to mannose-6-phosphate
on N-linked glycoproteins in the Golgi apparatus within cells.
 I-cell disease
• Individuals with I-cell disease are lacking the
phosphotransferase needed to phosphorylate the mannose
residues of potential lysosomal enzymes, causing the enzymes
to be secreted (by default), rather than being targeted to
lysosomal vesicles.
• I-cell disease is characterized by skeletal abnormalities,
restricted joint movement, coarse (dysmorphic) facial features,
and severe psychomotor impairment.
• Note: Because I-cell disease has features in common with the
mucopolysaccharidoses and sphingolipidoses, it is termed a
mucolipidosis.
• Currently, there is no cure, and death from cardiopulmonary
complications usually occurs by age 10 years.
• (Lippin)
I-cell disease
Inclusion cell (I-cell) disease results from
faulty targeting of lysosomal enzymes
• I-cell disease is a rare condition characterized by severe progressive
psychomotor retardation and a variety of physical signs, with death
often occurring in the first decade of life.
• Cells from patients with I-cell disease lack almost all of the normal
lysosomal enzymes; the lysosomes thus accumulate many different
types of undegraded molecules, forming inclusion bodies.
• The patients’ plasma contains very high activities of lysosomal
enzymes, suggesting that the enzymes are synthesized but fail to
reach their proper intracellular destination and are instead secreted.
• Mannose 6-phosphate serves to target enzymes into the lysosome.
(Harper)
• Lysosomal enzymes from normal individuals carry the
mannose 6-phosphate recognition marker, cells from
patients with I-cell disease lack the Golgi-located N-
acetylglucosamine phosphotransferase.
• Two lectins act as mannose 6-phosphate receptor
proteins; both function in the intracellular sorting of
lysosomal enzymes into clathrin coated vesicles in the
Golgi. These vesicles then leave the Golgi and fuse with a
prelysosomal compartment.
 Peroxisomal diseases
• Zellweger syndrome (ZS),
• Neonatal adrenoleukodystrophy, and
• Infantile Refsum disease (IRD)
• These three disorders are among a group of conditions called
Zellweger spectrum disorders that have overlapping symptoms
and affect many parts of the body.
 Zellweger syndrome
• Zellweger syndrome belongs to a group of diseases called
peroxisome biogenesis disorders (PBD). The diseases are
caused by defects in any one of the PEX genes that are
required for the normal formation and function of
peroxisomes.
• Severe Zellweger spectrum disorder involves distinctive facial
features, including a flattened face, broad nasal bridge ,
high forehead, and widely spaced eyes (hypertelorism ).
Children with severe Zellweger spectrum disorder typically do
not survive beyond the first year of life.
 Peroxisomal diseases
• Peroxisomal α-oxidation of fatty acids
• Branched-chain phytanic acid:
• This product of chlorophyll metabolism is not a substrate
for acyl CoA dehydrogenase because of the methyl group
on its β-carbon .
• Instead, it is hydroxylated at the α-carbon by phytanoyl
CoA α-hydroxylase (PhyH), carbon 1 is released as CO2,
and the product, 19-carbon pristanal, is oxidized to
pristanic acid, which is activated to its CoA derivative
and undergoes β-oxidation.
 Refsum disease
• Refsum disease is a rare, autosomal-recessive disorder
caused by a deficiency of peroxisomal PhyH (phytanoyl
CoA α-hydroxylase).
• This results in the accumulation of phytanic acid in the
plasma and tissues.
• The symptoms are primarily neurologic, and the
treatment involves dietary restriction to halt disease
progression.
 Refsum Disease
• Refsum disease is caused by a deficiency in a single
peroxisomal enzyme, the phytanoyl CoA hydroxylase that
carries out α-oxidation of phytanic acid. Symptoms include
retinitis pigmentosa, cerebellar ataxia, and chronic
polyneuropathy. Because phytanic acid is obtained solely from
the diet, placing patients on a low-phytanic acid diet has
resulted in marked improvement.
• (Marks)
Mitochondrial disorders
• Mutations in mitochondrial DNA result in a number of genetic
diseases that affect
skeletal muscle,
neuronal, and
renal tissues (known as mitochondrial disorders).
• Mitochondrial inheritance is maternal, as the sperm do not
contribute mitochondria to the fertilized egg.
• Spontaneous mutations within mitochondrial DNA have been
implicated with the mechanism of aging.
 Mitochondrial disorders
• MELAS (Mitochondrial Encephalopathy, Lactic
Acidosis, and Stroke-like episodes) syndrome is a rare
disorder that begins in childhood, usually between two
and fifteen years of age, and mostly affects the nervous
system and muscles.
• Alzheimer's disease.
• Muscular dystrophy.
• Lou Gehrig's disease.
• Diabetes.
• Cancer.
Endoplasmic reticulum storage diseases
• Diabetes, inflammation, and neurodegenerative disorders
including Alzheimer's disease, Parkinson's disease, and
bipolar disorder.
• Parkinson disease, a neurodegenerative movement disorder,
is due to insufficient dopamine production as a result of the
idiopathic loss of dopamine producing cells in the brain.
• Administration of L-DOPA (levodopa) is the most common
treatment.
• Dopamine cannot cross the blood brain barrier.
Synthesis of catecholamines
 Progeria
• Progeria (pro-JEER-e-uh), also known as Hutchinson-Gilford
syndrome, is an extremely rare, progressive genetic disorder
that causes children to age rapidly, starting in their first
two years of life.
• Children with progeria generally appear normal at birth.
 What is the cause of progeria?
• Progeria is caused by a change (mutation) in the LMNA gene
that codes for the lamin A protein.
• The lamin A protein is the scaffolding that holds the nucleus of
a cell together.
• Researchers now believe that the defective lamin A protein
makes the nucleus unstable
 How is progeria inherited?
• Almost all cases of progeria occur as a new, spontaneous (de
novo) mutation in the LMNA gene.
• This means there's no biological family history of the disease.
• It isn't inherited from a parent.
• The mutation nearly always occurs in the sperm cell before
conception
 Telomeres
• Telomeres may be viewed as mitotic clocks in that their length
in most cells is inversely related to the number of times the
cells have divided. The study of telomeres provides insight into
the biology of normal aging, diseases of premature aging (the
progerias) and cancer. (Lippin)
• An inability to replicate telomeres has been linked to cell aging
and death. Many somatic cells do not express telomerase;
when they are placed in culture, they survive a fixed number of
population doublings, enter senescence, and then die. Analysis
has shown significant telomere shortening in those cells.
• In contrast, stem cells do express telomerase and appear to
have an infinite lifetime in culture. Research is underway to
understand the role of telomeres in cell aging, growth, and
cancer.(Marks)