Proteins in the CNS
Structural proteins:
1. Neurofilaments
Molecular structure
Neurofilaments are intermediate filaments with a diameter of approximately 10 nm. They are heteropolymers composed of three major subunits: NFL (light chain), NFM (medium chain), and NFH (heavy chain). Each subunit contains a conserved α-helical rod domain that enables filament assembly, as well as variable C-terminal tail domains, particularly prominent in NFM and NFH, which are heavily phosphorylated. These projecting side arms play a key role in determining axonal caliber and the spacing between adjacent filaments.
Origin/biogenesis
Neurofilaments are synthesized in the neuronal soma (cell body) on free ribosomes, undergo post-translational phosphorylation within the axon, and are transported along microtubules by slow axonal transport mediated by kinesin and dynein motor proteins.
Disease associations
In amyotrophic lateral sclerosis (ALS), neurofilament aggregation and abnormal phosphorylation are prominent features, and neurofilament levels, particularly NFL and phosphorylated NFH (pNfH), serve as important biomarkers of axonal degeneration. In Charcot–Marie–Tooth disease, mutations in the NEFL gene lead to axonal neuropathy. Giant axonal neuropathy is characterized by defective intermediate filament organization due to mutations in gigaxonin. In traumatic brain injury, neurofilament light chain levels are elevated in blood and cerebrospinal fluid.
2. Tubulin
Molecular structure
Microtubules are hollow cylindrical structures approximately 25 nm in diameter, composed of α- and β-tubulin heterodimers. These dimers assemble head-to-tail into protofilaments, which associate laterally to form the microtubule wall. Multiple β-tubulin isotypes, such as TUBB2B and TUBB3, exist and confer region- and cell-specific properties to microtubules. A defining feature of microtubules is their dynamic instability, characterized by alternating phases of growth in the GTP-bound state and shrinkage in the GDP-bound state.
Origin/biogenesis
Microtubule proteins are synthesized in the neuronal soma and subsequently folded by chaperonins such as the CCT/TRiC complex. They undergo multiple post-translational modifications, including acetylation, detyrosination, and polyglutamylation, which are critical for regulating axonal transport, microtubule stability, and interactions with motor proteins.
Disease associations
Tubulinopathies caused by mutations in genes such as TUBB2B and TUBA1A lead to cortical malformations, including lissencephaly, polymicrogyria, and cerebellar hypoplasia. More broadly, defects in tubulin function contribute to neurodevelopmental disorders through impaired neuronal migration and axon guidance. In oncology, microtubule-targeting agents such as taxanes and vinca alkaloids commonly cause peripheral neuropathy as a dose-limiting toxicity. In neurodegenerative diseases, impaired microtubule stability plays an important role in the pathophysiology of disorders such as Alzheimer’s and Parkinson’s disease.
3. Actin
Molecular structure
Actin exists in two interconvertible forms: globular monomers (G-actin) and filamentous polymers (F-actin). Actin filaments are polarized structures in which the barbed (plus) end elongates more rapidly than the pointed (minus) end. Their assembly, disassembly, and organization are tightly regulated by actin-binding proteins, including cofilin, profilin, and the Arp2/3 complex. In neurons, actin is highly enriched in dendritic spines, presynaptic terminals, and growth cones, where it plays a central role in synaptic function and structural plasticity.
Origin/biogenesis
Actin is transcribed and translated in neurons, with additional local translation occurring in dendrites and axons. Intracellular calcium signaling, Rho family GTPases such as Rac1 and Cdc42, and activity-dependent synaptic signals tightly regulate its polymerization. Because of its rapid turnover, actin plays a central role in synaptic plasticity and dynamic remodeling of neuronal connections.
Disease associations
Mutations in ACTB and ACTG1 are associated with neurodevelopmental disorders, including Baraitser–Winter syndrome and other cortical malformations. Abnormal regulation of actin remodeling has also been implicated in cognitive disorders, including autism spectrum disorder and intellectual disability. In neurodegenerative conditions, cellular stress such as ischemia or Alzheimer’s disease can induce the formation of cofilin–actin rods, which disrupt intracellular transport and neuronal function. Additionally, mutations in ACTG1 affect actin organization in stereocilia and are a known cause of hereditary hearing loss.
4. Myelin proteins (MBP, PLP)
A. Myelin Basic Protein (MBP)
Molecular structure
Myelin basic protein is a highly positively charged, intrinsically disordered cytoplasmic protein that binds to negatively charged membrane lipids, thereby compacting the cytoplasmic surfaces of the myelin sheath and forming the characteristic central dense line.
Origin/biogenesis
Myelin basic protein is synthesized in oligodendrocytes, with its mRNA transported to developing myelin sheaths for localized translation. This spatial regulation helps prevent ectopic expression that could trigger an immune response. Multiple isoforms of the protein are generated through alternative splicing.
Disease associations
In multiple sclerosis (MS), myelin basic protein (MBP) is a major autoantigen, and demyelination exposes it to immune-mediated attack. In leukodystrophies, abnormal MBP expression disrupts proper myelin compaction. Following traumatic brain injury (TBI), MBP levels are elevated in cerebrospinal fluid, reflecting white matter damage.
B. Proteolipid Protein (PLP)
Molecular structure
Proteolipid protein is an integral transmembrane protein with four membrane-spanning domains. It is highly lipid-associated and constitutes the hydrophobic core of compact myelin. Two major isoforms, PLP1 and DM20, are produced through alternative splicing.
Origin/biogenesis
Proteolipid protein is synthesized in oligodendrocytes and trafficked through the endoplasmic reticulum and Golgi apparatus. Proper folding and membrane integration depend on glycosylation and lipid raft insertion.
Disease associations
Mutations or duplications of PLP1 cause Pelizaeus–Merzbacher disease (PMD), characterized by defective myelination, nystagmus, and hypotonia. In adults, PLP1 mutations can lead to spastic paraplegia type 2. Additionally, PLP degradation occurs in demyelinating lesions observed in multiple sclerosis and certain leukodystrophies.
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Enzymatic proteins
1. Tyrosine Hydroxylase (TH)
Molecular structure
Tyrosine hydroxylase is a tetrameric enzyme, with each subunit weighing approximately 60 kDa, that requires tetrahydrobiopterin (BH4) as a cofactor. Each subunit consists of a catalytic domain, which binds tyrosine and BH4, and a regulatory N-terminal domain containing phosphorylation sites. Tyrosine hydroxylase serves as the rate-limiting enzyme in the synthesis of catecholamines, including dopamine, norepinephrine, and epinephrine.
Origin/biogenesis
TH is primarily expressed in dopaminergic neurons of the substantia nigra and ventral tegmental area, noradrenergic neurons of the locus coeruleus, and in the adrenal medulla. Its transcription is regulated by neuronal activity, growth factors such as GDNF, and stress hormones. Post-translational regulation, particularly phosphorylation, enhances its catalytic activity.
Disease associations
In Parkinson’s disease, degeneration of tyrosine hydroxylase (TH)-positive neurons reduces TH levels in the nigrostriatal system. Dopa-responsive dystonia (Segawa disease) results from mutations in TH or defects in BH4 metabolism, causing decreased dopamine synthesis. Research has also linked altered TH expression to catecholaminergic dysregulation in conditions such as autism and ADHD. Exposure to neurotoxins, including MPTP and methamphetamine, can further decrease TH expression and enzymatic activity.
2. Glutamate Decarboxylase (GAD65 and GAD67)
Molecular structure
Glutamate decarboxylase (GAD) enzymes are pyridoxal phosphate (PLP)–dependent and exist in two major isoforms. GAD65, encoded by the GAD2 gene, is membrane-associated and concentrated in nerve terminals, whereas GAD67, encoded by the GAD1 gene, is cytosolic and accounts for the majority of baseline GABA synthesis. Both isoforms function as dimers, with a total molecular weight of approximately 140 kDa.
Origin/biogenesis
Glutamate decarboxylase is expressed in GABAergic neurons throughout the cortex, hippocampus, basal ganglia, and cerebellum. Its activity is regulated by neuronal activity and the availability of pyridoxal phosphate (vitamin B6). GAD65 undergoes palmitoylation, which targets it to synaptic vesicles for efficient GABA release.
Disease associations
Reduced expression of GAD67 is associated with impaired GABA synthesis and increased neuronal excitability in epilepsy. In stiff-person syndrome, autoimmune antibodies target GAD65, while GAD65 also serves as a major autoantigen in type 1 diabetes, affecting peripheral tissues rather than the CNS. Decreased GAD67 levels in parvalbumin-expressing interneurons have been observed in schizophrenia. Additionally, vitamin B6 deficiency in infants impairs GAD activity, leading to seizures.
3. Acetylcholinesterase (AChE)
Molecular structure
Acetylcholinesterase is a serine hydrolase located in synaptic clefts and at neuromuscular junctions. It exists in two main forms: tetramers anchored to membranes via PRiMA or collagen-like Q-subunits, and soluble monomers present in cerebrospinal fluid. Its catalytic site contains the characteristic Ser–His–Glu triad typical of esterases.
Origin/biogenesis
Acetylcholinesterase is synthesized in cholinergic neurons, including those of the basal forebrain and brainstem nuclei. The glycoprotein undergoes processing in the endoplasmic reticulum and Golgi apparatus before being trafficked to synapses. Its expression is tightly regulated to correspond with the density of cholinergic synapses.
Disease associations
In Alzheimer’s disease, acetylcholinesterase (AChE) levels are reduced in the cortex and hippocampus due to loss of cholinergic neurons, forming the basis for treatment with AChE inhibitors such as donepezil and rivastigmine. Organophosphate poisoning causes irreversible inhibition of AChE, leading to a cholinergic crisis. In myasthenia gravis, AChE inhibitors are used therapeutically to prolong the action of acetylcholine at neuromuscular junctions. Congenital AChE deficiency can result in prolonged apnea after succinylcholine administration.
4. Mitochondrial enzymes (representative examples)
A. Pyruvate Dehydrogenase Complex (PDH) Molecular structure Multienzyme complex with E1, E2, and E3 components. Requires thiamine, lipoic acid, FAD, NAD⁺, and CoA. Origin Nuclear-encoded, imported into mitochondria via TOM/TIM complexes. Disease associations PDH deficiency: lactic acidosis, neurodevelopmental delay. Mitochondrial disorders: impaired oxidative metabolism, energy failure in the CNS.
B. Cytochrome c Oxidase (Complex IV) Molecular structure Terminal enzyme of the electron transport chain. Contains heme a, heme a3, and copper centers (CuA, CuB). Origin Subunits are encoded by both mitochondrial DNA (mtDNA) and nuclear DNA. Disease associations Leigh syndrome, mitochondrial encephalomyopathies from Complex IV deficiency.
C. ATP Synthase Molecular structure F1 catalytic head + Fo proton channel. The rotational mechanism converts the proton gradient into ATP. Origin Assembled from nuclear and mtDNA-encoded subunits. Disease associations mtDNA mutations → energy failure, neuropathy, ataxia, encephalopathy.
D. Mitochondrial superoxide dismutase (MnSOD, SOD2) Molecular structure Homotetrameric enzyme in the mitochondrial matrix. Requires manganese. Disease associations Oxidative stress–related neurodegeneration (ALS, Parkinson’s). SOD2 deficiency is lethal without antioxidant rescue
