PNAS: Targeting SPOP proteins is expected to stop tau protein diseases, including Alzheimer's disease

In November, scientists reported that the drug lecanemab slowed the progression of
Alzheimer's disease.
Its effect was moderate, but it caused great excitement because it was the first time a drug had been shown to be able to affect the course
of this relentless incurable disease.

As a manufactured antibody, the drug lecanemab helps clear an abnormal protein called β amyloid (Aβ), which forms insoluble lumps around brain cells called amyloid plaques
.
It is thought that amyloid triggers and maintains the destruction of brain cells, leading to cognitive decline and ultimately dementia that plagues people with Alzheimer's disease
.

But many believe that for any treatment to have a significant impact on the course of Alzheimer's disease, they must also target a second protein that has so far received as much attention as Aβ: a protein
called tau.

Brian Kraemer, professor of medicine in the Department of Gerontology and Geriatrics at the University of Washington School of Medicine, said, "Amyloid plaques initiate a cascade of this disease, so it makes sense to try to eliminate them, but it's tau
that kills brain cells.
" ”

Kraemer specializes in neurodegenerative diseases caused by tau, known as tauopathy
.
These diseases include a long list of incurable neurodegenerative diseases
.
In some diseases, abnormal tau protein appears to be the main cause
of the disease.
These disorders are called pure tauopathy
.
They include frontotemporal lobar degeneration, progressive supranuclear palsy, and Pick's disease
.
Alzheimer's disease, on the other hand, is called mixed tauopathy because Aβ also plays a role
.

The protein tau stabilizes key structures
called microtubules within cells.
These structures act as the internal skeleton of the cell and act as conduits
for the cell to transport material from one place to another.

In Alzheimer's disease and other tau proteinopathy, tau is defective
.
It separates from the microtubules, forming insoluble aggregates within the cell, called nerve fiber tangles
.
The rupture of microtubules and the accumulation of nerve fiber tangles disrupt the ability of brain cells to function and eventually lead to cell death
.

Kraemer said, "If we want to target any one of the targets in Alzheimer's disease, we should probably target tau
.
It is strongly associated with
a decline in cognitive dysfunction.
You want to get rid of amyloid, but what you really want is to maintain cognitive abilities
.
This requires targeting tau
.
”

In a new study, Kraemer and his team identified a protein
that appears to be crucial for the formation of abnormal tau aggregates.
They found that by blocking the genes needed to produce the protein, it was possible to prevent the accumulation
of tau in animal models.
The results of the study were published online in the journal PNAS on December 27, 2022, under the title "SPOP loss of function protects against tauopathy.
"

The protein is called SPOP (speckle-type POZ protein).

The name indicates that it is found in the spot-like compartment of the cell, and that it contains a special amino acid fragment
called the POZ domain.
This is one of
several proteins Kraemer and his colleagues found related to tau protein disease.
Another protein, called SUT-2 (suppressor of tauopathy-2), is being explored for therapeutic potential
.

The exact role SPOP plays in tau-related diseases is unclear
.
But it appears to be involved in an important process by which cells process
and eliminate defective proteins.
Their findings suggest that if drugs that inhibit the action of this protein can be developed, it may be possible to treat Alzheimer's disease and other tau protein pathies
.

To identify these key regulatory proteins, Kraemer and his colleagues used an animal model
his lab constructed two decades ago.
The model is a genetically engineered version
of a small nematode --- Caenorhabditis elegans, which is commonly found in soil, ---.
Caenorhabditis elegans only has a lifespan of about three weeks, making it ideal for
studying how genetic mutations affect growth, development, and function throughout an organism's lifespan.

To build this model, Kraemer and his team introduced the human tau protein-coding gene into the nematodes
.
In their experiments, the authors confirmed that this nematode model exhibits many of the abnormalities seen in human tau protein diseases: accumulation of insoluble tau, progressive nerve cell death, behavioral defects, and shortened
lifespan.

In tau transgenic animals, SPOP-1 overexpression increased larval lethality
.
Image from PNAS, 2022, doi:10.
1073/pnas.
2207250120
.

The authors then screened all the genes in this nematode model to see if randomly knocking out any one of them prevented the changes
.
This approach allowed them to identify the SUT-2 gene first and, more recently, the SPOP gene
.

Randall Eck, first author of the paper and a graduate student in neuroscience at the University of Washington School of Medicine, said, "When we eliminated the SPOP protein in this nematode model, we saw a dramatic reduction in tau accumulation and progressive nerve cell death, as well as improved behavioral deficits and lifespan
.
”

Kraemer, Eck and other researchers in the field are now studying whether their findings in animal models of this nematode can be translated into a treatment
in humans.
The first step is to see if inhibiting these genes can produce similar protective effects
in a mouse model of the disease.
Research to inhibit the SUT-2 gene is promising, while research on SPOP is
ongoing.

Kraemer said, "We are still in the early stages
of developing effective Alzheimer's disease remission.
TAU inhibitors may be sufficient to treat pure tau proteinopathy, but for Alzheimer's disease, I think we have to target both tau and amyloid to get an effective treatment
.
(Biovalley Bioon.
com)

Resources:

Randall J.
Eck et al.
 SPOP loss of function protects against tauopathy.
PNAS, 2022, doi:10.
1073/pnas.
2207250120.