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BY DR. DOUGLAS WATT, PH.D.
A complex multi-syndrome family of neurodegenerative disorders: many questions, few answers
By Douglas F. Watt, Ph.D.
Adjunct Professor, Graduate Department of Psychology Lesley University
Clinical Neuroscience Advisor, 9th Dimension Biotech, Inc.
In this review we will explore the confusing and complex umbrella concepts surrounding the
frontotemporal dementia family, which has recently been united with the ALS group. This super
category thus includes an enormous spectrum of clinical phenotypes, including progressive
supranuclear palsy, corticobasal degeneration, two forms of primary progressive aphasia, the
classic behavioral variant frontotemporal dementia (the most common of all of these), something
called LATE (‘limbic age-related tar DNA binding protein encephalopathy’), ALS, and admixtures of
these various clinical syndromes with ALS or some lesser form of motor neuron disease. This
overarching superordinate concept of the FTLD/ALS family was created in part due to the
discovery that 95% of ALS patients show deposition of the most common proteinopathy in FTD,
along with the frequent clinical finding that patients can start out with motor neuron disease and
over time progress to one of the FTLD syndromes, or conversely, start with one of the
frontotemporal syndromes and then segue towards motor neuron failure. This creates clinical
courses sometimes characterized by “phenotypic dedifferentiation.”
This umbrella concept of FTLD/ALS thus forms the largest, most confusing, and most diverse
family of neurodegenerative disorders, and this phenotypic diversity and histopathological and
genetic diversity remains to be fully explained in terms of how such diverse genetic and sporadic
causes can yield a family of shared syndromes and proteinopathies. This family of disorders is
characterized by three forms of proteinopathy: ubiquitinated tar-DNA binding protein, tauopathy
including Picks's bodies, and a more rarely found ubiquitinated ‘fused-in-sarcoma’ proteinopathy.
Some of the multivariate clinical phenotypes tend to more commonly load on one particular
proteinopathy versus another, but in general, most clinical phenotypes can present with any of
these three proteinopathies, particularly the common behavioral variant FTD. There are also a
handful of mutations that appear to be responsible for almost all of the autosomal dominant forms
of these frontotemporal/ALS syndromes: mutations in progranulin, in tau, and in a chromosome 9
‘open reading frame’ gene characterized by pathogenic repeats in ‘intron’ areas. FTLD/ALS shows
a higher percentage of disease associated with a clear pathogenic mutation than any other
neurodegenerative family, but still, most of the disease is sporadic. All of these concepts are
challenging and even esoteric notions, particularly for newcomers to the field, that we will have to
unpack and demystify, making the FTLD/ALS family one of the most challenging for clinicians,
students, and patients and their families to understand.
In any case, from mechanistic standpoint, this diverse family of disorders may show failure in RNA
processing and derailment of the critical RNA lifecycle as a/the principal neurodegenerative
stressor. Both fused in sarcoma protein and TAR DNA binding protein are critical RNA binding
proteins that operate throughout the RNA lifecycle and support both maturation, inhibition, and
other forms of modulation of transcription and translation – a failure that strikes at the core of the
cell and its biologic work. Although they shuttle back and forth typically between the nucleus and
cytoplasm, they are found pathologically aggregated in the cytoplasm, suggesting failure of the
nuclear shuttle process, which is still somewhat mysterious. As in other neurodegenerative
disorders, we have once again an incomplete understanding of precisely what is driving
neurodegeneration in this family of disorders, including an unclear, but probably nontrivial burden
from disinhibited inflammatory process/gliosis. Additionally, the appearance of TAR DNA binding
protein in other neurodegenerative disorders challenges our popular boxology models and forces
us to consider a bigger picture or more global ‘field theory’ of neurodegeneration. Therapeutic opportunities remain virtuallY completely undefined, beyond the modestly to minimally successful
symptomatic psychopharmacologic approaches, including promotion of progranulin (unclear how to
do this but is AdpN a promotor?), exploration of multiple CR mimetics (which may take a ‘load’ off
the RNA transcript process via mTOR inhibition while upregulating autophagy and modulating
inflammation). Many more questions than answers, but yet despite this, there has been enormous
progress in the last 10 years.
These statements have not been evaluated by the FDA. This product is not intended to diagnose, treat, cure, or prevent any disease.
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