Huntingtin-associated protein 1
Encyclopedia
Huntingtin-associated protein 1 (HAP1) is a protein
which in humans is encoded by the HAP1 gene
. This protein was found to bind to the mutant huntingtin
protein (mHtt) in proportion to the number of glutamines present in the glutamine repeat region.
Huntington's disease
(HD), a neurodegenerative disorder characterized by loss of striatal
neuron
s, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with huntingtin, with two cytoskeletal proteins (dynactin
and pericentriolar autoantigen protein 1
), and with a hepatocyte growth factor-regulated tyrosine kinase substrate (HGS
). The interactions with cytoskeletal proteins and a kinase substrate suggest a role for this protein in vesicular trafficking or organelle transport.
of dividing striatal cells, and associated endosome
s, microtubule
s and vesicles
in the basal forebrain and striatial neurons – where HAP1B is preferentially expressed. Furthermore, Page and colleagues identified HAP1 mRNA in the following forebrain limbic nuclei: amygdala
, nucleus accumbens
, dentate gyrus
, septal nuclei
, bed nucleus of the stria terminalis and hypothalamus
. They also identified HAP1 in numerous areas of the cortex
, including the anterior cingulated cortex and the limbic cortex.
The subcellular location of HAP1 closely resembles that of Htt. Gutekunst and colleagues used immunogold labeling to identify subcellular localization of both HAP1 and muHtt, and identified a close similarity of the distribution of the two proteins. They did not find HAP1 labeling in protein aggregates in the cytoplasm
and postulated that this indicated HAP1 in pre-aggregate related HD pathogenesis
.
The role of HAP1 in HD pathogenesis may involve aberration of cell cycle
processes, as high immunostaining of HAP1 during the cell cycle has been observed. It may have a part in spindle orientation, microtubule stabilization or chromosome movement. More importantly, HAP1 may also disrupt endocytosis
, as it has been detected on vesicles involved in the early stages of this process. It is possible that the non-pathogenic activity of HAP1 is intracellular trafficking and that this is perturbed following its association with mHtt. HAP1 also interacts with proteins other than Htt and it is likely that their function is altered in HD pathogenesis. These include dynactin p150Glued, a cytoplasmic dynein accessory protein involved in retrograde transport of organelles, and kinesin-like protein which is another transport-mediation protein.
HAP1 also shows a similar CNS distribution pattern to that of neural nitric oxide synthase (nNos
), especially in both of the pedunculopontine nuclei
, the supraoptic nucleus
, and the olfactory bulb
. The possible significance of this interaction is that increased HAP1 interaction with muHtt may also increase nitric oxide (NO) thus facilitating neuronal damage.
HAP1 also interacts with other factors involved in vesicular trafficking including GABAA receptor,
Rho-GEF
, and HGS
.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
which in humans is encoded by the HAP1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. This protein was found to bind to the mutant huntingtin
Huntingtin
The Huntingtin gene, also called HTT or HD gene, is the IT15 gene which codes for a protein called the huntingtin protein...
protein (mHtt) in proportion to the number of glutamines present in the glutamine repeat region.
Huntington's disease
Huntington's disease
Huntington's disease, chorea, or disorder , is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea...
(HD), a neurodegenerative disorder characterized by loss of striatal
Striatum
The striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
neuron
Neuron
A neuron is an electrically excitable cell that processes and transmits information by electrical and chemical signaling. Chemical signaling occurs via synapses, specialized connections with other cells. Neurons connect to each other to form networks. Neurons are the core components of the nervous...
s, is caused by an expansion of a polyglutamine tract in the HD protein huntingtin. This gene encodes a protein that interacts with huntingtin, with two cytoskeletal proteins (dynactin
Dynactin
Dynactin or Dynein activator complex is a multi-subunit protein found in eukaryotic cells that aids in bidirectional intracellular transport by binding to dynein and Kinesin II and linking them to the organelle or vesicle to be transported....
and pericentriolar autoantigen protein 1
PCM1
Pericentriolar material 1, also known as PCM1, is a protein which in humans is encoded by the PCM1 gene.- Function :The PCM1 protein was originally identified by virtue of its distinct cell cycle-dependent association with the centrosome complex and microtubules. The protein appears to associate...
), and with a hepatocyte growth factor-regulated tyrosine kinase substrate (HGS
HGS (gene)
Hepatocyte growth factor-regulated tyrosine kinase substrate is an enzyme that in humans is encoded by the HGS gene.-Interactions:HGS has been shown to interact with TSG101, STAM2, Merlin, DLG4, IL2RB, EPS15, CLTC and Signal transducing adaptor molecule.-Further reading:...
). The interactions with cytoskeletal proteins and a kinase substrate suggest a role for this protein in vesicular trafficking or organelle transport.
Function
HAP1 preferentially interacts with muHtt in a polyQ dependent manner. Its localization and possible interacting partners (other than Htt) have since been characterised, thus elucidating a possible role for this protein in HD pathogenesis. Martin et al. showed that HAP1 is localized in mitotic spindleMitotic spindle
In cell biology, the spindle fibers are the structure that separates the chromosomes into the daughter cells during cell division. It is part of the cytoskeleton in eukaryotic cells...
of dividing striatal cells, and associated endosome
Endosome
In biology, an endosome is a membrane-bound compartment inside eukaryotic cells. It is a compartment of the endocytic membrane transport pathway from the plasma membrane to the lysosome. Molecules internalized from the plasma membrane can follow this pathway all the way to lysosomes for...
s, microtubule
Microtubule
Microtubules are a component of the cytoskeleton. These rope-like polymers of tubulin can grow as long as 25 micrometers and are highly dynamic. The outer diameter of microtubule is about 25 nm. Microtubules are important for maintaining cell structure, providing platforms for intracellular...
s and vesicles
Vesicle (biology)
A vesicle is a bubble of liquid within another liquid, a supramolecular assembly made up of many different molecules. More technically, a vesicle is a small membrane-enclosed sack that can store or transport substances. Vesicles can form naturally because of the properties of lipid membranes , or...
in the basal forebrain and striatial neurons – where HAP1B is preferentially expressed. Furthermore, Page and colleagues identified HAP1 mRNA in the following forebrain limbic nuclei: amygdala
Amygdala
The ' are almond-shaped groups of nuclei located deep within the medial temporal lobes of the brain in complex vertebrates, including humans. Shown in research to perform a primary role in the processing and memory of emotional reactions, the amygdalae are considered part of the limbic system.-...
, nucleus accumbens
Nucleus accumbens
The nucleus accumbens , also known as the accumbens nucleus or as the nucleus accumbens septi , is a collection of neurons and forms the main part of the ventral striatum...
, dentate gyrus
Dentate gyrus
The dentate gyrus is part of the hippocampal formation. It is thought to contribute to new memories as well as other functional roles. It is notable as being one of a select few brain structures currently known to have high rates of neurogenesis in adult rats, .The dentate gyrus cells receive...
, septal nuclei
Septal nuclei
The septal area are structures that lie below the rostrum of corpus callosum in front of lamina terminalis , composed of medium-size neurons grouped into medial, lateral, and posterior groups...
, bed nucleus of the stria terminalis and hypothalamus
Hypothalamus
The Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
. They also identified HAP1 in numerous areas of the cortex
Cerebral cortex
The cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
, including the anterior cingulated cortex and the limbic cortex.
The subcellular location of HAP1 closely resembles that of Htt. Gutekunst and colleagues used immunogold labeling to identify subcellular localization of both HAP1 and muHtt, and identified a close similarity of the distribution of the two proteins. They did not find HAP1 labeling in protein aggregates in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
and postulated that this indicated HAP1 in pre-aggregate related HD pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
.
The role of HAP1 in HD pathogenesis may involve aberration of cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
processes, as high immunostaining of HAP1 during the cell cycle has been observed. It may have a part in spindle orientation, microtubule stabilization or chromosome movement. More importantly, HAP1 may also disrupt endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
, as it has been detected on vesicles involved in the early stages of this process. It is possible that the non-pathogenic activity of HAP1 is intracellular trafficking and that this is perturbed following its association with mHtt. HAP1 also interacts with proteins other than Htt and it is likely that their function is altered in HD pathogenesis. These include dynactin p150Glued, a cytoplasmic dynein accessory protein involved in retrograde transport of organelles, and kinesin-like protein which is another transport-mediation protein.
HAP1 also shows a similar CNS distribution pattern to that of neural nitric oxide synthase (nNos
NOS1
Nitric oxide synthase 1 , also known as NOS1, is an enzyme that in humans is encoded by the NOS1 gene.- Function :Nitric oxide is a messenger molecule with diverse functions throughout the body...
), especially in both of the pedunculopontine nuclei
Pedunculopontine nucleus
The pedunculopontine nucleus is located in the brainstem, caudal to the substantia nigra and adjacent to the superior cerebellar peduncle. It has two divisions, one containing cholinergic neurons, the pars compacta, and one containing mostly glutamatergic neurons, the pars dissipata...
, the supraoptic nucleus
Supraoptic nucleus
The supraoptic nucleus is a nucleus of magnocellular neurosecretory cells in the hypothalamus of the mammalian brain. The nucleus is situated at the base of the brain, adjacent to the optic chiasm...
, and the olfactory bulb
Olfactory bulb
The olfactory bulb is a structure of the vertebrate forebrain involved in olfaction, the perception of odors.-Anatomy:In most vertebrates, the olfactory bulb is the most rostral part of the brain. In humans, however, the olfactory bulb is on the inferior side of the brain...
. The possible significance of this interaction is that increased HAP1 interaction with muHtt may also increase nitric oxide (NO) thus facilitating neuronal damage.
HAP1 also interacts with other factors involved in vesicular trafficking including GABAA receptor,
Rho-GEF
ARHGEF1
Rho guanine nucleotide exchange factor 1 is a protein that in humans is encoded by the ARHGEF1 gene.-Interactions:ARHGEF1 has been shown to interact with GNA13, CD44, P110α and GNA12.-Further reading:...
, and HGS
HGS (gene)
Hepatocyte growth factor-regulated tyrosine kinase substrate is an enzyme that in humans is encoded by the HGS gene.-Interactions:HGS has been shown to interact with TSG101, STAM2, Merlin, DLG4, IL2RB, EPS15, CLTC and Signal transducing adaptor molecule.-Further reading:...
.