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Neurofilament homeostasis and
motoneurone degeneration
Carla Perrone Capano,
1,2
* Roberto Pernas-Alonso,
1
and Umberto di Porzio
1
Summary
Neurofilament disorganisation is a hallmark of various
neurodegenerative diseases. We review here current
knowledge of neurofilament structure, gene expression
and function. Neurofilament involvement in motoneurone
neurological diseases is discussed in view of recent data
from transgenic and spontaneous mouse mutants. In the
mammalian neurone, the three neurofilament subunits
are assembled into intermediate filaments as obligate
heteropolymers. The subunits are expressed differen-
tially during development and adult life according to the
cell type and its physiological state. In addition to the
well-established role of neurofilaments in the control of
axonal calibre, there is increasing evidence that neurofi-
laments can interact with other cytoskeletal components
and can modulate the axoplasmic flow. Although the
extent to which neurofilament abnormalities contribute
to the pathogenesis in human diseases remains un-
known, emerging evidence suggests that disorganised
neurofilaments can provoke degeneration and death of
neurones. BioEssays 23:24±33, 2001.
ß 2001 John Wiley & Sons, Inc.
Introduction
Neurofilaments were discovered more than a century ago, by
the founders of neuroanatomy. In 1887 Ramon y Cajal stained
brain specimens by the Golgi technique of silver impregnation
(``reazione nera'') and later wrote in his autobiography that
nerve cells appeared ``coloured brownish black even to their
finest branchlets, standing out with unsurpassable clarity upon
a transparent yellow background. All was sharp as a sketch
with Chinese ink.'' He had seen the thin fibrous structures
called ``neurofibrils'', which earliest physiologists had inter-
preted as artefacts of fixation. From this, Cajal deduced that
neurones are morphologically independent units and are
individual cells, and he formulated the ``neurone theory''.
(1)
Decades later, the fibrous structures were identified by
electron microscopy in unfixed preparations
(2)
and became
known as neurofilaments (Fig. 1A±C). In recent years,
neurofilaments have also been molecularly identified.
Neurofilaments are 10 nm in diameter, intermediate in size
between actin filaments (about 5 nm) and microtubules (about
20 nm). They thus fall into the general class of cytoskeletal
components known as intermediate filaments (IFs). Members
of the IF superfamily exhibit cell-type-specific patterns of
expression and perform specialised and tissue-specific func-
tions, as well as a role in the cell's mechanical integrity.
Neurofilaments and other neuronal IF proteins, such as
peripherin and a-internexin are present throughout axogen-
esis in different neurones.
(3)
The complex composition and
regulation of IFs suggest that they do more than serve as a
structural scaffold inside the nerve cells. Unlike other IFs, NF
proteins (NFs) consist of three different polypeptides with a
large carboxyl-terminal tail domain. In mammals, the NF triplet
comprises proteins with molecular weights of about 68, 150
and 200 kDa known as light (NFL), medium (NFM) and high
(NFH) subunit, respectively (Fig. 1D,E). Assembled as
obligate heteropolymers, NFs are the most abundant cytos-
keletal components in large neurones and myelinated axons,
particularly those arising from large lower and upper motor and
sensory neurones
(3)
(Fig. 1B).
Neurofilaments frequently appear altered in different
neurodegenerative diseases
(4)
including hereditary motoneur-
one diseases such as amyotrophic lateral sclerosis (ALS) and
spinal muscular atrophy (SMA). Analysis of various mouse
strains with spontaneous or induced neurological mutations
indicates that abnormalities in neurofilaments can provoke
selective degeneration and death of motoneurones.
(5)
Thus,
the susceptibility to the deleterious effects of NF accumulation
shows remarkable cellular selectivity, indicating that transcrip-
tional and/or post-transcriptional/post-translational mechan-
isms regulating these ``panneuronal'' genes can differ among
24 BioEssays 23.1 BioEssays 23:24±33, ß 2001 John Wiley & Sons, Inc.
1
International Institute of Genetics and Biophysics, CNR, via Marconi
12, 80125 Naples, Italy.
2
University of Catanzaro, Magna Grecia, Faculty of Pharmacy, 88021
Roccelletta di Borgia (CZ), Italy.
Funding agencies: Telethon (Grant no. 625); CNR target project
Biotecnologie; CNR Progetto Strategico Neurodegenerazione; Pro-
gramma Ricerca Scientifica Regione Campania.
*Correspondence to: Dr. Carla Perrone Capano, International Institute
of Genetics and Biophysics, CNR, via Marconi 12, 80125 Naples, Italy.
E-mail: perrone@iigb.na.cnr.it
Abbreviations: ALS, amyotrophic lateral sclerosis; E, embryonic day;
IF, intermediate filament; NF, neurofilament protein, NFL, NF light
subunit; NFM, NF medium subunit; NFH, NF high subunit, PK, protein
kinases; RNP, ribonucleoprotein; SMA, spinal muscular atrophy; KSP,
sequence motif Lys-Ser-Pro; SMN, survival motoneurone gene;
SOD1, Zn, Cu superoxide dismutase 1 gene
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